International Journal of

Molecular Sciences

Review
Peptides Derived from Growth Factors to Treat
Alzheimer’s Disease
Suzanne Gascon 1 , Jessica Jann 1 , Chloé Langlois-Blais 2 , Mélanie Plourde 3,4 , Christine Lavoie 2,5, * and
Nathalie Faucheux 1,5, *

1 Laboratory of Cell-Biomaterial Biohybrid Systems, Department of Chemical and Biotechnological

Engineering, 2500 Boulevard Université, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada;
Suzanne.Gascon@USherbrooke.ca (S.G.); Jessica.Jann@usherbrooke.ca (J.J.)
2 Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé,
Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; Chloe.Langlois.Blais@USherbrooke.ca
3 Centre de Recherche sur le Vieillissement, Centre Intégré Universitaire de Santé et Services Sociaux de
l’Estrie–Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1G 1B1, Canada;
Melanie.Plourde2@USherbrooke.ca
4 Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke,
Sherbrooke, QC J1H 5N4, Canada
5 Institut de Pharmacologie de Sherbrooke, 3001 12th Avenue, N., Sherbrooke, QC J1H 5N4, Canada
* Correspondence: Christine.L.Lavoie@USherbrooke.ca (C.L.); Nathalie.Faucheux@USherbrooke.ca (N.F.);
Tel.: +1-819-821-8000 (ext. 72732) (C.L.); +1-819-821-8000 (ext. 61343) (N.F.)

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by

progressive neuron losses in memory-related brain structures. The classical features of AD are a



dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary


tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the
Citation: Gascon, S.; Jann, J.;
disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration
Langlois-Blais, C.; Plourde, M.;
of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However,
Lavoie, C.; Faucheux, N. Peptides
their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use.
Derived from Growth Factors to Treat
Alzheimer’s Disease. Int. J. Mol. Sci.
To overcome these limitations, short peptides mimicking the binding receptor sites of these growth
2021, 22, 6071. https://doi.org/ factors have been developed. Such peptides can target selective signaling pathways involved in
10.3390/ijms22116071 neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and
their derived peptides as potential treatment for AD. It describes (1) the physiological functions of
Academic Editor: growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies
Cristina Martínez-Villaluenga to develop peptides derived from growth factor and their capacity to mimic the role of native proteins;
and (3) new advancements and potential in using these molecules as therapeutic treatments for AD,
Received: 15 May 2021 as well as their limitations.
Accepted: 1 June 2021
Published: 4 June 2021
Keywords: neurotrophin; bone morphogenetic proteins; MAPK; PI3K/AKT; cholinergic neurons;
amyloid-β peptide; tau protein; metabolic pathway
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a pro-
gressive decline of cognitive and behavioral functions, with typical symptoms such as
memory loss and language or problem-solving difficulties [1]. AD is the leading cause of
Copyright: © 2021 by the authors.
dementia, accounting for 60 to 80% of cases, and currently affects more than 50 million
Licensee MDPI, Basel, Switzerland.
people worldwide [1]. Moreover, the World Health Organization (WHO) estimates that
This article is an open access article
distributed under the terms and
131 million people will suffer from AD by 2050 [2], ensuring a global public health priority.
conditions of the Creative Commons
The etiology of AD is associated with changes in synaptic signaling, loss of synapses,
Attribution (CC BY) license (https:// and neuron degeneration [3]. It has long been reported that the dysregulation of the
creativecommons.org/licenses/by/ cholinergic system in the basal forebrain, a master regulator of executive and mnemonic
4.0/). functions, is linked to memory loss/cognitive decline in AD [4,5]. The cortical cholinergic

Int. J. Mol. Sci. 2021, 22, 6071. https://doi.org/10.3390/ijms22116071 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021, 22, 6071 2 of 44

denervation remains one of the earliest, most severe, and most consistent transmitter
changes observed during AD progression, which led to the formulation of the “cholinergic
hypothesis” [6].
The histological hallmarks of AD are the accumulation of dense extracellular deposits,
also known as senile/amyloid plaques, and intracellular neurofibrillary tangles in several
brain regions such as the basal forebrain, frontal lobe, hippocampus, cingulate gyrus, amyg-
dala, substantia nigra, several brainstem nuclei, and the cerebral cortex [7]. The amyloid
plaques are caused by the accumulation and aggregation of amyloid-β (Aβ) peptides
(mainly Aβ1–42 but also Aβ1–40 peptides) generated by the consecutive cleavage of the
amyloid-β precursor protein (APP) by β- and γ-secretases [8]. The neurofibrillary tangles
are formed when the neuronal microtubule-associated protein tau is abnormally hyperphos-
phorylated by kinases such as glycogen synthase kinase 3β (GSK3β), leading to its release
from the microtubule and intracellular aggregation into bundles of filaments [9]. It causes
neuronal dysfunctions such as axon integrity and vesicular transport impairment [9,10].
The “amyloid hypothesis” (also known as the amyloid cascade hypothesis) has been
the mainstream explanation for the pathogenesis of AD for over 25 years, but is still a
highly controversial topic in the field. This hypothesis suggests that the accumulation
and deposition of Aβ peptides is the initiating factor that triggers a cascade of disease-
causing processes such as tau-tangle formation, neuroinflammation, synapse dysfunction,
and cell death, which ultimately leads to dementia [11]. Despite ongoing debates about
this hypothesis, evidence supports the idea that an imbalance between production and
clearance of Aβ peptides is the initiating event of AD pathogenic processes [12]. The
strongest evidence is that all the dominant mutations causing the familial (early onset,
Mendelian-inheritance) form of AD reside either in APP or presenilin (catalytic subunit of
γ-secretase), and result in increased production of Aβ1–42 or self-aggregation propensity of
resultant Aβ peptides [11]. The overexpression of APP due to duplication of chromosome
21 in trisomy 21 (Down’s syndrome) has also been reported to cause an early appearance of
Aβ1–42 plaques and development of AD at an early age (about 50% of people with Down
syndrome who are in their 60s have AD) [1]. Furthermore, the amyloid hypothesis is
also strongly supported by the identification of protective mutation of APP that results in
lifelong decrease in APP cleavage into Aβ and reduced risk of AD [13]. While these genetic
modifications greatly increase the AD risk, they are rare (1–6% of AD cases) [14]. Indeed,
more than 95% of AD cases belong to the sporadic (late onset) form of AD (LOAD), which
is caused by complex genetic and environmental factors. Apolipoprotein E4 (APOE4) is the
most prevalent and important genetic risk factor for LOAD [15], with an estimated 3 to 12
times increased risk of LOAD [1]. APOE4 has been reported to have both amyloid-related
and amyloid-independent effects, including reduced Aβ clearance by the blood–brain
barrier (BBB) and decreased Aβ plaque load, tau tangle formation, and regulation of
microglia linked to the triggering receptor expressed on myeloid cells 2 (TREM2) (also
linked with high risk of LOAD [16]), proinflammatory activation, impaired glucose and
lipid metabolism, and compromised vascular homeostasis [17–19]. Furthermore, several
genome-wide association (GWAS) studies identified multiple AD-risk genes that could
be linked with the Aβ cascade and/or tau pathology, but also to cholesterol and lipid
metabolism, immune system and inflammatory response, and vesicle trafficking [20–22].
These reports highlight the complexity and multifactorial nature of AD.

2. Current Strategies Targeting AD Development

Current treatments of AD only alleviate symptoms for a short period, and there is
still no cure for this disease or a way to stop or delay its progression. Presently, the only
Food and Drug Administration (FDA)-approved treatments for AD are primarily acetyl-
cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), targeting the cholin-
ergic system dysfunction [1,23] and memantine, an antagonist of the N-methyl-D-aspartate
receptor (NMDAR) involved in chronic excitotoxicity and synaptic dysfunction [1,24].
Int. J. Mol. Sci. 2021, 22, 6071 3 of 44

However, these treatments have only modest and transient effects, and do not stop the
progression of the disease [25,26].
In recent decades, many therapeutic approaches targeted the amyloid cascade com-
ponents. Consequently, many clinical trials have been directed toward Aβ-lowering
strategies, including interference with the amyloidogenic processing of APP, mainly with
β- and γ-secretase inhibitors, and removing Aβ oligomers and plaques with monoclonal
antibodies [22,27]. Unfortunately, until now, no therapy directed at reducing Aβ has been
successful, resulting in either no cognitive benefit, or even worsening cognitive outcome
or inducing major side effects [28–31]. However, a recent phase 2 trial of Donanemab, a
humanized IgG1 antibody that targets a modified form of Aβ present only in established
plaques, showed modest inhibition of cognitive and functional decline in early symp-
tomatic AD patients [32]. While encouraging, longer and larger trials are necessary to
study the efficacy and safety of Donanemab in AD. Therapeutic strategies targeting tau
are also under investigation, including inhibitors of tau kinases and tau aggregation, and
immunotherapy [27,33]. As for Aβ-target therapies, none of the tau-targeted therapies
have been successful yet, and the only treatment that has reached a phase III trial is the tau
aggregation inhibitor TRx0237 (LMTX™) [33].
Given that therapeutics targeting the main components of the Aβ cascade hypothesis
failed in the late stage of clinical trials, these strategies have been reconsidered, and
other strategies are being developed. Multiple promising targets to prevent AD or its
progression have been identified [34]. The neuroinflammatory system, including astrocyte
and microglia (key cellular regulators of neuroinflammation), and genetic variants linked
to neuroinflammation, such as TREM2, have received great attention recently due to
the notable correlation between the degree of neuroinflammation and the severity of
AD [27,35,36]. Targeting, APOE; a major lipid transporter that plays a pivotal role in
the development, maintenance, and repair of the central nervous system, and which
polymorphism is a major risk factor for developing LOAD, is also in an early phase of
therapeutic development [17,19,37]. Given that neurotrophin deficiency and dysregulation
is closely associated with the pathogenesis of AD [38], supplementation of neurotrophic
factors (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) is
currently a potential therapeutic approach to treat AD [27]. Using AD animal models,
this treatment has proven its efficacy to ameliorate learning deficit [39,40]. A phase II
clinical trial using adenoviral vector to deliver NGF (AAV2-NGF) to the basal forebrain
(a region rich in cholinergic neurons) of AD patients demonstrated the feasibility of this
approach [41]. The sections below describe the role of different growth factors in the central
nervous system (CNS), their alteration in AD pathology, and potential uses as therapeutic
treatments for AD.

3. Growth Factors in Brain Function and AD

3.1. Neurotrophins
The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), and neurotrophin-
4/5 (NT-4/5). Besides being essential during the development of the nervous system, they
play a crucial role in the survival and phenotype maintenance and regeneration of specific
types of neurons into adulthood [42]. In addition, they are implicated in the pathogenesis of
certain neurodegenerative diseases, such as AD, and are thus targeted as potential therapeutic
solutions for this disease.

3.1.1. Structure
The human NGF gene is located on the proximal short arm of chromosome 1 (1p),
while human BDNF, NT-3, and NT-4/5 genes are located on chromosome 11 (11p), 12 (12p),
and 19 (19q) respectively [43,44]. The BDNF gene has a very complex structure [45,46]. The
human BDNF gene consists of nine functional promoters and one protein-coding 30 exon
that is spliced together with one of the nine noncoding 50 exons or two noncoding exons
unique to humans (Vh and VIIIh), leading to several mRNA splice variants [46]. The splice
Int. J. Mol. Sci. 2021, 22, 6071 4 of 44

variants are expressed in response to specific stimuli [47]. For example, the translation of
Bdnf transcripts containing exon-IV and -VI is directly or indirectly regulated by changes
in neuronal activity, and may be linked to pathologies related to depression and memory
disorders in the rat model [48–50]. The expression of specific Bdnf exons is regulated by
epigenetic mechanisms in the adult rat brain during memory consolidation [51].
After synthesis in the endoplasmic reticulum, the precursor form of neurotrophin
includes a signal sequence and a prodomain, followed by the mature protein sequence.
The prodomain is cleaved intracellularly and/or extracellularly to release the mature
protein. The cleavage of proNGF to obtain the mature form of NGF (mNGF) involves a
CNS extracellular protease cascade leading to the activation of plasmin [52]. Both proNGF
and mNGF are biologically active and can induce an antagonist effect on the maintenance
of the cholinergic neuron phenotype [53]. Mature neurotrophin can also be degraded
by enzymes such as matrix metalloprotease-9 (MMP-9) [52]. The process leading to the
maturation of proNGF to mNGF, as well as the degradation of mNGF by MMP, is called
the NGF metabolic pathway [54,55].
The mature neurotrophins are evolutionarily conserved with a high sequence homol-
ogy between vertebrates [43,56]. In addition, the mature NGF, BDNF, NT-3, and NT-4/-5
share 50% amino acid residue identity [57]. They also associate noncovalently into ho-
modimers, with each monomer presenting a cysteine “knot” with the characteristic loop
formation and a tertiary fold. These monomers (118 or 119 amino acids) are characterized
by seven β-strands connected by three exposed β-turn loops (L1, L2, L4) and an additional
loop L3 (Figure 1) [58,59]. All of these exposed sites may be accessible for interaction with
neurotrophin receptors.

Figure 1. Structure of (A) mNGF (PDB ID: 1 BET) monomer [60]. The exposed β-turn loops L1 (residues 28-36), L2 (residues
42-49), L3 (residues 59-67) and L4 (residues 91-99) were used to design peptides. (B) The mNGF dimer (red and blue)-TrkA
extracellular domain (black) binding sites (PDB ID: 2IFG [61]) [58,62].

3.1.2. Neurotrophin Receptors and Signal Transduction

The neurotrophin homodimers interact with two distinct classes of receptors: p75 neu-
rotrophin receptor (p75NTR), which is a member of the tumor necrosis receptor superfamily,
and tropomyosin receptor kinase (Trk) (Figure 1) [63]. Sortilin, a member of the Vps10p-
domain family of transmembrane receptors, acts as a coreceptor of p75NTR [64].
The Trk family is composed of three Tyr kinase receptors: TrkA, TrkB, and TrkC. TrkA
is expressed in the cortex and hippocampus, while TrkB and TrkC are expressed in both
axonal and dendritic compartments in hippocampal, cortical, and cerebellar neurons [65].
Int. J. Mol. Sci. 2021, 22, 6071 5 of 44

The p75NTR receptor can interact with all neurotrophins in their pro- and mature
forms [64]. TrkA mainly recognizes NGF, whereas BDNF and NT-4/5 interact with TrkB,
and NT-3 binds TrkC; p75NTR regulates the specificity as well as affinity of Trk receptors
for their neurotrophin ligands [66]. The affinity of NGF for both p75NTR and TrkA is quite
similar (Kd around 1–2 nM) [64,67]. However, TrkA receptors co-expressed with p75NTR
have a higher affinity for NGF (Kd 2.8 × 10−12 M) [67].
The extracellular domain of p75NTR consists of four cysteine-repeat domains, with
two of them being implicated in the interaction with neurotrophins. The mNGF has two
binding epitopes for p75NTR: the first one involves positively charged residues in L1 and
L4 loops, whereas the second one involves hydrophilic residues from the highly conserved
loop L3 and the C-terminus [68]. The p75NTR receptor also has single transmembrane and
cytoplasmic domains, the latter containing a “death domain”.
The extracellular domain of TrkA contains three leucine-rich 24-residue motifs (LRR1-
3) flanked by two cysteine clusters (CR). Two immunoglobulin-like C2-type domains (Ig-C2)
are adjacent to these structures. Using the crystal structure of NGF/TrkA-d5 complex at
2.2 Å resolution, Wiesmann et al. found that the Ig-C2 domain (TrkA-d5) closest to the cell
membrane is sufficient for the binding of mNGF through its L2 and L4 loops [68]. Each Trk
receptor also has single transmembrane and cytoplasmic domains. The latter contains the
tyrosine (Tyr) kinase activity region surrounded by phospho-Tyr residues involved in the
recruitment of signaling and adaptor proteins of specific signaling cascades [63]. However,
the tyrosine kinase domain is missing in some isoforms of TrkB and TrkC [69].
Upon binding, NGF and BDNF induce the dimerization of their cognate Trk full-length
(Trk-FL) receptors. The cytoplasmic kinase domain of Trk receptors is in turn activated, and
an autophosphorylation of their tyrosine residues occurs. These phosphorylations trigger
the specific recruitment of adaptor proteins, the proto-oncogene tyrosine-protein kinase
Src homology 2 domain containing (Shc), the fibroblast growth factor receptor substrate 2
(FRS2), and the phospholipase Cγ (PLCγ) (Figure 2).
Int. J. Mol. Sci. 2021, 22, 6071 6 of 44

Figure 2. The NGF and BDNF signaling pathways and their roles in healthy and AD brains [70–75]. CAM: calmodulin kinase; DAG: diacylglycerol; mBDNF: mature form of BDNF
(monomer); mNGF: mature form of NGF (monomer); RSK: ribosomal S6 kinase; TRAF: TNFR-associated factors. The figure was created using Servier Medical Art (https://smart.servier.com;
30 April 2021).
Int. J. Mol. Sci. 2021, 22, 6071 7 of 44

Following this recruitment, Shc is Tyr-phosphorylated and stimulates the mitogen-

activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK1/2) and phos-
phoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways [76]. The Ras/MAPK/ERK1/2
pathway induces the activation of the transcription factor cAMP response element-binding
protein (CREB), which is critical for early-response gene expression (e.g., c-Fos). Furthermore,
NGF, through the MAPK/ERK1/2 pathway, potentiates TrkA transcription by the homeobox
transcription factor LIM homeobox 8 (Lhx8) [77].
The adaptor protein PLCγ cleaves phospholipids to generate two second messen-
gers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), respectively leading to
intracellular release of Ca2+ /calmodulin kinase (CAM) activation and protein kinase C
(PKC)-mediated signaling. The PLCγ1/Ca2+ CAM/CREB pathway is involved in synaptic
plasticity [78].
A transactivation of the Trk-FL receptors can also be initiated by G-protein-coupled
receptors (GPCRs) such as adenosine A2A receptors [79]. Such transactivation can favor a
neuroprotective effect [80].
While commonly considered dominant-negative receptor isoforms unable to signal,
truncated TrkB, such as TrkB.t1 (which has a truncated C-terminal domain), inhibits Rho
GTPase signaling by interacting with the Rho GDP dissociation inhibitor (RhoGDI1) [81–83].
This inhibition induces cytoskeletal rearrangement in neuronal cells [82]. However, the
truncated Trk signaling and function in normal brain and neuropathologic conditions are
complex and still under investigation (for a review, see [84]).
The p75NTR receptor has no intrinsic catalytic activity, but upon mature neurotrophin
binding, its cytoplasmic domain can interact with adaptor proteins to activate downstream
signaling molecules, including nuclear factor kB (NF-kB). Binding of pro-neurotrophin to
p75NTR activates the JNK-caspase-3 mediated pathway, NF-κB pathway, and RhoA path-
way [85,86]. However, the BDNF Val66Met polymorphism alters its prodomain structure,
inducing different bioactivity due to impaired interaction with the sortilin receptor [87].
Both proBDNF and the mature form of BDNF (mBDNF) can also have an antago-
nist effect by binding with high affinity to p75NTR-sortilin and TrkB, respectively [88]:
proBDNF/p75NTR-sortilin induces neuronal apoptosis [89], whereas mBDNF/TrkB pro-
tect the hippocampal neurons from glutamate-induced cell death [90,91]. An imbalance in
the proBDNF:mBDNF ratio may therefore be involved in neuronal degeneration.

3.1.3. Effects of Neurotrophins on the CNS Cells

• NGF
While BDNF mRNA in the adult human brain is found in the hippocampus, cerebral
cortex, hypothalamus, and cerebellum, NGF mRNA is mainly expressed in the cortex
and hippocampus [46,92,93]. The NGF-responsive neurons in the CNS are the cholinergic
neurons of the basal forebrain (BFCNs) and striatum. The BFCNs, which possess extended
axons throughout the hippocampus and neocortex, play a crucial role in learning and mem-
ory functions [94,95]. NGF, after its release by the postsynaptic cortical and hippocampal
neurons, binds to TrkA and is retrogradely transported along the axon to the BFCN bodies.
It can then initiate signaling cascades, leading to the maintenance of BDNF phenotype in
adult CNS [55,96]. Indeed, NGF/TrkA signaling ensures the activation of genes encoding
for cholinergic differentiation markers such as acetylcholine synthesis enzyme (ChAT) and
the vesicular acetylcholine transporter (VAChT) [97]. Nevertheless, while the hippocam-
pus of P20–P25 homozygous TrkA knockout mice (TrkA−/− ) presents a great deficit in
cholinergic fiber density, the cholinergic innervation of 28-day-old NGF knockout mice
is not altered [98,99]. Importantly, Eu et al. recently reported a decrease in cholinergic
fiber density in the hippocampus, but not in the cortex of 12-week-old Ngf gene knockout
mice [100] (Table 1). An atrophy and loss of septal cholinergic neurons with deficits in
memory and learning were also observed in heterozygous mutant mice (NGF+/– ), which
showed a decreased level of both NGF mRNA and protein [101]. In addition, chronic
inhibition of the maturation of proNGF (but not proBDNF) with α2 -antiplasmin treatment
Int. J. Mol. Sci. 2021, 22, 6071 8 of 44

in the medial prefrontal cortex of normal adult rats led to a local loss and atrophy of
cholinergic terminals paralleled by cognitive impairment. Interestingly, the number of
dopaminergic, noradrenergic, glutamatergic, and GABAergic boutons were not affected.
This cholinergic degeneration prevents the consolidation and retrieval of a new memory in
rats [102].
Int. J. Mol. Sci. 2021, 22, 6071 9 of 44

Table 1. Effect of the growth factor superfamily on CNS cells and their potential effect on Alzheimer’s disease hallmarks.

Superfamily Experimental Conditions Effect on CNS Cells In Vitro or In vivo Refs

Neurotrophin
Animal: Homozygous Ngf −/−
knockout or WT mice Ngf cKO mice:
C57BL/6 ↓ Hippocampal Ngf mRNA level
NGF ↓ Adult hippocampal neurogenesis [100]
Treatment: Injection of viral vector for Ngf overexpression
↓ Cholinergic fiber density in the hippocampus but not in the cortex
under stereotaxic guide
NGF restores hippocampal cholinergic fiber innervations and spatial memory.
BDNF + ADTC5 compared to BDNF alone or vehicle:
Animal: Female APP.PS1 transgenic mice
↑ Cognitive performance (Y-maze and new object recognition)
Treatment: BDNF at 5.7 nmol/kg, BDNF + ADTC5 ↑ Degree of neuron-glial antigen 2 (NG2) receptor expression a marker for oligodendrocyte maturation
[103]
(modulator to allow BDNF to pass BBB) at 10 µmol/kg or ↑ Hippocampus level of early growth response 1 (EGR1) and activity-related cytoskeleton-associated
BDNF vehicle. Intravenous injection every 4 days for 8 injections protein mRNA transcripts
No significant impact on Aβ plaque
Animal: AD11 anti-NGF mice (sporadic AD model), 6
Rescue memory performance (object recognition and object context tests)
months old
[104]
Treatment: Intranasal delivery at 12.6, 42, and 420 No impact on Ab plaques, tau hyperphosphorylation and cholinergic deficit
pmol/administration, repeated 7 times for 15 days ↓ CD11b-positive microglia in the hippocampus
BMP
Cells: neuronal progenitor cells from adult rat (NPC) Aβ1-42 : ↑ BMP-6 level
[105]
BMP-6 Treatment: 50–100 ng/mL for 4 days with a refresh of
BMP-6: ↓ Proliferation of NPC (dose dependent effect)
medium containing BMP-6 at 2 days
↓ Number Aβ amyloid plaques in AD model
Animal: APP.PS1/CHGFP (AD model) and WT/CHGFP
↑ ChAT expression in APP.PS1/CHGFP and WT/CHGFP
(control) transgenic mice 5 and 10 months old
↑ Density of cholinergic fibers in APP.PS1/CHGFP and WT/CHGFP
[106]
↑ Hippocampal level of receptors TrkA and p75NTR in 5 months old mice but not in 10 months old mice
Treatment: intraventricular infusion at 4 ng/h for 7 days ↑ Hippocampal level of NGF in both mice (15–20%)
↑ IGF-1 levels in 5 months APP.PS1/CHGFP
BMP-9
Improve spatial and associative learning and memory (Morris water maze, contextual fear
Animal: APP/PS1 mice (7 months) conditioning test)
↓ Aβ levels and number of plaques in AD model
↓ Hyperphosphorylated tau in the cortex and hippocampus [107]
Treatment: intranasal delivery of 50 ng/g/d for 30 days ↓ Neuroinflammation (activated microglia and astrocytes)
↑ Expression of low-density lipoprotein receptor-related protein 1 (LRP1), involved in the clearance of
Ab
Int. J. Mol. Sci. 2021, 22, 6071 10 of 44

Table 1. Cont.

Superfamily Experimental Conditions Effect on CNS Cells In Vitro or In vivo Refs

IGF
Animal: Tg2576 AD mouse (10 months old) and WT C57BL/6 ↓ Oxidative stress
mouse (control) ↑ Expression of PI3K, AKT and CREB in hippocampus ↓ levels of amyloid plaques in the
hippocampus [108]
↑ Memory consolidation (Morris Water Maze) via PI3K/AKT pathway
Treatment: Injection saline/DMSO (control) and IGF-2 at 250 ng
↓ Memory decline
IGF-2 ↓ Aβ plaque numbers
Animal: APP.PS1/CHGFP and Wild Type (control) mice ↑ p75NGFR compared to vehicle both in APP.PS1/CHGFP and WT
↑ ChAT in APP.PS1/CHGFP and WT hippocampus
↑ BMP-9 level in APP.PS1/CHGFP and WT hippocampus (basal level is higher in [109]
APP.PS1/CHGFP)
Treatment: Infusion of vehicle or 50 ng/h hIGF-2 for 7 days ↓ ALK1 expression in WT but not in APP.PS1/CHGFP hippocampus
↓ FGF-2 level in APP.PS1/CHGFP hippocampus
↑ Hippocampal neurogenesis (DCX) in APP.PS1/CHGFP and WT hippocampus
FGF
Animal: APP.PS1 mice (AD model) and WT Tg2576 In vivo:
mice (control). FGF-2 in APP.PS1 mice
Treatment: hippocampal injection of hybrid virus expressing Reverse learning deficit memory
FGF-2 or GFP (control) at 1 × 1010 per brain at 4 months ↓ Aβ hippocampal deposition
(presymptomatic) and 7–8 months (postsymptomatic) of age ↑ Neurogenesis in subgranular zone of dental gyrus [110]
Cells: Primary microglia culture and neural stem cells (mouse In vitro:
embryonic brain day 14) FGF-2
FGF-2
Treatment: Microglia: FGF-2 (0.1 or 1 ng/mL) + 10 µg fibrillar ↑ Dose-dependent Aβ phagocytosis in microglia
Aβ1–42 for 1 h ↓ Production of Aβ in neural stem cells
Neural stem cell: hybrid virus + 1 µM Aβ1–42 oligomer for 7 days ↑ Neuronal differentiation of neural stem cells
LMW and HMW FGF-2:
Cells: Primary astrocyte culture weight FGF-2 (HMW, 23 kDa) at
Induce ERK and AKT pathway activation
10 ng/mL
Protective effect against cytotoxicity induced by Aβ (20 µM) or oxidative stress
[111]
↑ Bcl-XL transcripts
Treatment: Medium with or without purified low molecular
LMW FGF-2:
weight FGF-2 (LMW, 17 kDa) or high molecular
↑ Proliferation by upregulation of c-Myc, Cyclin D1, and Cyclin E through PI3K/AKT pathway
Int. J. Mol. Sci. 2021, 22, 6071 11 of 44

Table 1. Cont.

Superfamily Experimental Conditions Effect on CNS Cells In Vitro or In vivo Refs

In vivo:
Subcutaneous injection:
Animal: male APP.PS1 transgenic mice (6 months old)
↑ Learning abilities after 5 days (Morris water maze)
↓ Brain Aβ burden
↓ Tau phosphorylation positive area
Treatment: Subcutaneously injection with 5 mg/kg/day twice a
Intracerebroventricular injection:
FGF-21 day for 1 month or intracerebroventricular with a mini pump 0.4 [112]
Rescue neurodegeneration through the FGF-21/FGFR1 signaling pathway (Morris water Maze)
µg/day for 14 days
In vitro:
↑ Cell viability against Aβ25-35 toxicity (higher effect in the presence of astrocytes)
Cells: Rat (PC12) pheochromocytoma cells and rat astrocyte (C6)
↓ Tau hyperphosphorylation
line in coculture treated with FGF-21 at different concentrations
↓ ROS levels
between 0.07 and 8 µM
Rescues the lactate system deficiency induced by Aβ25–35
Int. J. Mol. Sci. 2021, 22, 6071 12 of 44

• BDNF
BDNF has an important role in synaptic plasticity, including long-term potentiation
(LTP) in the hippocampus of the adult brain, and is therefore involved in learning and mem-
ory consolidation [113,114]. BDNF is produced in the entorhinal cortex and then undergoes
anterograde transport to the hippocampus [115]. mRNA expression encoding BDNF is
increased in the hippocampus of rats that acquired spatial memory [116]. Moreover, using
a hidden-platform water-maze task, Gorski et al. found that forebrain-restricted BDNF
mutant mice (Emx-BDNFKO) present profound impairments in hippocampus-dependent
learning [117]. Furthermore, BDNF can regulate the expression of two ionotropic glutamate
receptors important for LTP: the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
(AMPA) and NMDAR [118].
Importantly, recent studies showed that the ratio of proBDNF to mBDNF is important
for the synaptic plasticity. APOE4 epigenetically prevents BDNF transcription through
the nuclear translocation of histone deacetylases 4 and 6 in human neurons [119]. It can
also block the secretion and conversion of proBDNF to mBDNF [120]. Unlike mBDNF,
proBDNF decreases the strength of the synapses [54,121].

3.1.4. Effects of Neurotrophins on AD Hallmarks

• NGF
NGF mRNA levels are not decreased in the cerebral cortex of patients suffering from
AD [122,123]. In contrast, using regional hippocampal dissections, Ginsberg et al. observed
a downregulation of mRNAs for NGF and TrkA in patients suffering from mild cognitive
impairment or AD compared to healthy subjects [124].
Recent studies highlight the role played by the NGF metabolic pathway, which is
strongly affected in AD, leading to an imbalance in the proNGF:mNGF ratio [54,125]. The
degradation of mNGF is promoted in AD due to an increase in MMP-9 activity, while the
proNGF level is enhanced [126–129]. Indeed, an inhibition of the plasminogen activator
factor in AD brain prevents the cleavage of proNGF to NGF by extracellular plasmin [130].
Unlike TrkA, the expression of p75NTR is not altered in BFCNs during the progression
of the dementia [131]. An increase in the proNGF:mNGF ratio has been shown to be
sufficient to alter the phenotype of BFCNs, inducing a downregulation of TrkA and ChAT
protein expression, as well as degenerative retrograde alterations at their somatodendritic
level [53]. Furthermore, proNGF extracted from AD frontal cortex can induce apoptosis
in 3T3 cells expressing human p75NTR, while no effect was induced by proNGF isolated
from a comparably aged control brain. This apoptosis depends on the γ secretase shedding
of p75NTR [132]. The activation of PI3K/AKT and MEK/ERK pathways downstream of
Trk was shown to prevent the apoptosis induced by proNGF [133].
Furthermore, NGF binding to TrkA has been suggested to promote the amyloidogenic
cleavage of APP. A loss of the NGF/TrkA signaling could be linked to amyloid peptide
deposition and tau abnormalities [134].
The use of exogenous mature NGF to restore the cholinergic system and treat AD hall-
marks has therefore drawn considerable attention (for a review, see [5,55,135]). However,
the delivery of NGF to brain neurons via peripheral vein administration is limited due
to its molecular weight (despite its 13 kDa) and polarity that limit its transport across the
BBB [136,137]. Furthermore, NGF had a plasma half-life of 7.2 min (normal adult rat) [136],
and its intravenous administration in healthy human subjects can initiate diffuse myalgias
in neck and throat muscles [138].
Intraventricular NGF administrations were therefore used to bypass the BBB and
directly target the brain. For example, Hefti et al. performed repeated intraventricu-
lar injection of NGF (10 µg, twice weekly for 4 weeks) in adult rats with partial lesions
of the cholinergic septo-hippocampal pathway. They observed a significant increase in
hippocampal ChAT activity on the lesioned sides treated by NGF in comparison to the
untreated ones [139]. Moreover, mouse NGF or recombinant human NGF (rhNGF, 625
µg per intraventricular injection for a total of eight injections) in monkeys prevents the
Int. J. Mol. Sci. 2021, 22, 6071 13 of 44

progressive degenerative changes that occur in BFCNs following transection of their axons
in the fornix [140,141]. A limited clinical trial of intracerebroventricular NGF adminis-
tration (up to 3 months) on three patients suffering from AD did not demonstrate clear
cognitive amelioration, although a few neuropsychology tests showed slight improvements.
Unfortunately, several negative side effects, such as back pain and weight loss, were also
reported [142].
The success of NGF approach strongly depends on the spatial and temporal delivery
of the neurotrophins that must be controlled to avoid any side effect as described above [55].
The efficiency of other routes of NGF administration, such as intraocular or intranasal de-
livery, are still under investigation [143,144]. Other approaches based on NGF gene therapy
include stereotactic surgery [145] or cell therapy [146]. Rafii et al. showed that bilateral
stereotactic administration of adeno-associated virus serotype 2 delivering NGF (AAV2-
NGF) to the nucleus basalis of Meynert can induce the synthesis of biologically active NGF
without adverse events [145]. Nevertheless, no conclusion on cognitive outcomes arises
from this study due to the small number of participants and lack of prospective control
subjects [145]. A phase II clinical trial that included 49 AD patients recently confirmed that
AAV2-NGF delivery was well-tolerated over 2 years, but no clinical cognitive outcomes
were observed compared to the control group [41]. The use of transplanted cells (NGF
cell therapy) also requires more studies on the inflammatory responses induced in the
brain [147].
Thus, there are important challenges remaining in using NGF treatment, but there is
still enthusiasm regarding this strategy for treating AD patients.
• BDNF
Several studies have shown that BDNF gene expression, as well as proBDNF and
mBDNF levels, are decreased in the cortex, hippocampus, and basal forebrain in AD-
affected brains [148–151] (Table 1). The decrease in BDNF expression appears to correlate
with the degree of cognitive deficits in humans [152]. TrkB mRNA levels are downregulated
in patients suffering from both mild cognitive impairment and AD compared to healthy
patients in both CA1 pyramidal neurons and regional hippocampal dissections [124]. TrkB
downregulation also correlates with the abundance of neuritic plaques and neurofibrillary
tangles [153]. Several BDNF-mediated functions are altered in AD by β-amyloid peptides,
as well as tau pathology, through the glucocorticoid receptor pathway [154,155]. The
BDNF signaling impairment induced by Aβ might involve NMDAR dysregulation [156].
Interestingly, Aβ selectively increases mRNA levels for the truncated TrkB, and induces
the cleavage of TrkB by calpain [157]. The truncated TrkB:TrkB-FL ratio is increased in
hippocampal and cortical postmortem samples from AD subjects [148,149].
Since altered BDNF/TrkB signaling has been involved in AD pathology, various
therapeutic approaches, such as exogenous mature BDNF delivery, BDNF gene therapy,
and cell therapy, have been investigated [158,159]. Interestingly, unlike NGF, BDNF can
cross the BBB in a bidirectional manner [160] However, the BBB penetration of BDNF
remains low [136]. Therefore, some BBB modulators, such as cadherin peptides (ADTC5),
have been used to improve BDNF’s efficiency in crossing the BBB. Intravenous injection of
BDNF with ADTC5 in transgenic APP.PS1 mice improved the cognitive performance of
these AD mice compared to BDNF alone [103].
Some promising results were also observed using Bdnf gene therapy in aged nonhu-
man primates. The BDNF-treated monkeys showed a significant improvement in perfor-
mance of their visuospatial discrimination tasks [159].
Braschi et al. also recently found that intranasal delivery of BDNF at 42 pmol can
rescue memory performance of AD11 mice, a sporadic model of AD. Surprisingly, this
treatment has no effect on Aβ burden, tau hyperphosphorylation, or cholinergic deficit,
whereas it induces a drastic decrease of CD11b immunoreactive brain microglia [104].
However, the comparison with human is difficult, since aging human and the murine
microglia signature strongly diverge [161]. For example, the proportion of morphologically
activated microglia in postmortem human cortical tissue is correlated with the accumula-
Int. J. Mol. Sci. 2021, 22, 6071 14 of 44

tion of pathologic characteristic of AD, such as the number of amyloid plaques and tau
accumulation, worsening the cognitive decline [162]. However, such results open new
perspectives on the use of BDNF to treat AD.

3.2. The Bone Morphogenetic Protein (BMP)

BMPs/growth differentiation factors (GDFs) belong to the transforming growth factor-
β (TGF-β) superfamily (for a review, see [163]). Other members of this superfamily include
the TGF-β (TGF-β 1-3), nodal, activins, glial-derived neurotrophic factor (GDNF) family,
and anti-Müllerian hormone/Müllerian inhibiting substance. BMPs are classified into
four subgroups in function of their sequence homology: (I) BMP-2/BMP-4 Drosophila
decapentaplegic (dpp) subgroup (92% amino acid identities); (II) BMP-5/BMP-6/BMP-
7/BMP-8 Drosophila 60A subgroup (less than 65% residue identities with BMP-2); (III)
BMP-9/BMP-10 subgroup; (IV) BMP-12/BMP-13/BMP-14/) subgroup [164,165]. BMPs
are well known for their involvement in bone formation and remodelling [163]. However,
studies using knockout mice highlighted that BMPs have a crucial role in eye, kidney, brain,
and heart development [166–169].

3.2.1. Pro-BMP and Mature BMP Complexes

As already described for neurotrophins, pre-pro-BMPs contain a signal peptide (22
amino acid residues, pre-pro-BMP-9), a prodomain for folding and secretion (297 residues,
BMP-9 prodomain), and a mature BMP domain (BMP) (110 residues, BMP-9) [170]. After
signal-peptide removal, the pro-BMPs form dimers that are then cleaved by furin, favoring
the formation of complexes by noncovalent association between the prodomain fragments
and BMP [170]. After secretion, the pro-BMP/BMP complexes interact with extracellular
matrix proteins to obtain a latent cross-armed conformation [171].

3.2.2. BMP Receptors and Signal Transduction

BMP homodimer or heterodimer act on cells by binding to the heterotetrameric com-
plex, comprising two dimers of Type I and Type II Ser/Thr kinase receptors (Figure 3) [172].
BMP dimers interact with Type I kinase receptors by their wrist epitopes, and Type II
kinase receptors by their knuckle epitope [165,173,174]. These Type I or Type II receptors
are characterized by a BMP-binding extracellular domain at their N-terminal extremity, a
single pass transmembrane region, and a C-terminal intracellular domain containing the
Ser/Thr kinase activity [175,176].
Members of the BMP family interact with three Type I (BMPR-1A or ALK3; BMPR-1B
or ALK6; type 1A activin receptor ActR-1A or ALK2) and three Type II (BMPRII, ActRIIA
and ActRIIB) Ser/Thr kinase receptors. Furthermore, BMP-9 can bind with a high affinity to
another Type I Ser/Thr kinase receptor called ALK1 [165,173,177,178]. Most of Type I and
Type II BMP receptors are present in the brain. BMPRII receptors are abundant in the cortex
and hippocampus [179]. ALK-3 receptors are expressed in adult hippocampus-derived
neural stem cells and astrocytes in the dentate gyrus and the hilar region, while ALK-6
expression is found in mature neurons [180]. BMP dimer binding to Type I and Type II
Ser/Thr kinase receptors activates the canonical small mothers against decapentaplegic
(Smad) 1/5/8 and/or MAPK signaling pathways [181–183]. Upon binding to BMP, the
Type II receptors phosphorylate the Type I receptors at their GS motif. The activated
Type I receptors phosphorylate, in turn, Smad 1, 5, or 8, which form a complex with
Smad4. The Smad complexes are then translocated to the nucleus, where they interact
with transcriptional coactivators to promote gene transcription such as Id1-4 [180,184]. For
example, BMP-9 induces the phosphorylation and nuclear translocation of Smad1/5/8
in SH-SY5Y cells [185]. The canonical Smad1/5/8 pathway is strongly regulated. Its
activation can be prevented by several mechanisms, such as extracellular antagonists of
BMP (Gremlin, Noggin, Chordin) [181], and the decreased surface availability of Type
I and Type II kinase receptors due to their internalization through clathrin-dependent
mechanisms [183]. The inactive membrane receptor BAMBI (decoy-receptor BMP and
Int. J. Mol. Sci. 2021, 22, 6071 15 of 44

activin membrane-bound protein) can also block BMP signaling [186]. Other regulatory
molecules of this signaling pathway act intracellularly. The pSmad1/5/8 can be deactivated
via their dephosphorylation by phosphatases such as the protein phosphatase magnesium-
dependent 1A (PPM1A). The canonical Smad pathway can also be inhibited by inhibitory
Smad (I-Smad, Smad6/7) [187]. BMP2/4 can induce the upregulation of genes encoding
for I-Smad in adult hippocampus-derived neural stem cells [180,187].
Int. J. Mol. Sci. 2021, 22, 6071 16 of 44

Figure 3. FGF-2 and BMP-9 signaling pathways and their roles in healthy and AD brains [106,185,188–192]. GAB1: Grb2-associated binder-1; SOS: salt overly sensitive; TAB1/2/3:
TAK1 binding protein 1/2/3; TAK: transforming growth factor β-activated kinase 1; XIAP: X-linked inhibitor of apoptosis. The figure was created using Servier Medical Art
(https://smart.servier.com; 30 April 2021).
Int. J. Mol. Sci. 2021, 22, 6071 17 of 44

3.2.3. Effect of BMP on CNS

Members of subgroup I (BMP-2/BMP-4) and II (BMP-5/BMP-6/BMP-7/BMP-8) are
found in the hippocampus and/or cerebral cortex of adult brain [179,184,193–196]. For
example, in adult rat brain, BMP-5 is widely expressed in neurons, astrocytes, ependymal
cells, and meninges [196]; BMP-6 in astrocytes, ependymal cells, and oligodendrocytes [197];
whereas BMP-9 is detected in the spinal cord and septal area [198,199].
BMPs are involved in multiple events during the CNS formation and patterning
(for a review, see [200]). However, even though several BMPs are widely expressed
throughout the adult CNS, their role in its maintenance is still poorly understood [201].
Mira et al. found that BMP-2 dose-dependently decreases the percentage of proliferating
adult hippocampus-derived neural stem cells cultured in medium supplemented with
fibroblast growth factor 2 (FGF-2) [180]. BMP-4 also decreases the number of neural stem
cells that enter the cell cycle. The deletion of both Bmpr1a and Smad4 genes in these neural
stem cells confirms that BMPR1a-Smad4 signaling is involved in cell quiescence induced
by BMP-2/BMP-4 [180].
Among BMPs, BMP-9 has generated a great interest since it promotes BFCN dif-
ferentiation and maintenance, and may also prevent cerebral ischemia–reperfusion in-
juries [188–190,202] (Table 1). BMP-9 favors the differentiation of mouse septal neurons
into the cholinergic phenotype both in vitro and in vivo, and increases the production
of the neurotransmitter acetylcholine [188,198]. BMP-9 can also induce an increase in
mRNA levels of Idb1 and Idb3 transcriptional regulators, fibroblast growth factor receptor
3 (FGFR3), and BMPRIa within 48 h in dissociated septal cells from embryonic day 14
mice [188].
Furthermore, intracerebroventricular administration of BMP-9 (16 ng/µL (8 ng/h)
over a 6-day period prevents the loss of cholinergic neurons after a septo-hippocampal
transection in mice. It increases the expression of NGF and its receptors, p75NTR and TrkA
in hippocampus [203].

3.2.4. Effect of BMP on AD Hallmarks

Increases in Bmp2, Bmp4, and Bmp6 transcript levels have been reported in hippocampi
of aged mice. Both BMP-4 and BMP-6 protein levels are more abundant in the cortex of old
mice [204]. An upregulation of BMP-6 mRNA levels was also observed in the hippocampus
and cortex of patients with AD [105]. Crews et al. suggested that BMP-6 in AD may
have deleterious effects on adult hippocampal neurogenesis due to its inhibitory effect
on stem cell proliferation [105]. Aβ1–42 -containing plaques appear to play a key role
in BMP-6 upregulation in AD, increasing BMP-6 mRNA and protein expression in the
neural progenitor cells (Table 1) [105]. In the same way, an increase in BMP-4 levels was
correlated with reduced hippocampal cell proliferation in a mouse model of AD [205]. The
involvement of BMPs in CNS and neurodegenerative disorders such as AD is still under
investigation [200].
Several studies have shown that BMP-9 might be a promising molecule to treat
AD [106]. Using a AD mouse model (APP.PS1), which exhibit cholinergic defects, high
accumulation of amyloid plaques, and cognitive impairments, Burke et al. found that
intracerebroventricular infusion of BMP-9 (4 ng/h) for 7 days can reduce Aβ42-positive
plaques in the cortex and hippocampus [106]. This treatment also favors the establishment
of a trophic environment for BFCNs in the hippocampus by upregulating the expression of
NGF, its receptors (p75NTR, TrkA), NT-3, and insulin-like growth factor 1 (IGF-1) [106].
Wang et al. have recently confirmed that BMP-9 injected intranasally into APP.PS1 mice
(50 ng/g/d for 30 days), reduces senile plaque accumulation and restore cognitive func-
tion [107]. In addition, GSK3β, one of the kinases involved in the hyperphosphorylation
of tau, is inhibited by its phosphorylation at Ser9 in the brain of BMP-9-treated mice. In-
deed, the level of hyperphosphorylated tau in neurons in the cortex and hippocampus is
decreased in BMP-9-treated APP.PS1 mice [107].
Int. J. Mol. Sci. 2021, 22, 6071 18 of 44

Therefore, BMP-9, through its action on BFCN, might be a promising molecule to treat
AD. In addition, its receptor ALK1 is not affected at the early stage of AD [206]. However,
BMP-9 acts as a dimer of around 24 kDa that cannot easily cross the BBB, and the use of
supraphysiological doses is not only very expensive, but more importantly, may induce
side effects.

3.3. FGF and Other Growth Factors

3.3.1. FGF
To date, there are 22 mammalian FGFs (for a review, see [207]). They are classified
into seven subfamilies based on their sequence homology and phylogeny involving the
canonical FGFs, endocrine FGFs, and intracellular FGFs (for a review, see [208]). In human,
FGF-2 has five isoforms of different molecular weights (18 kDa, 21 kDa, 22.5 kDa, 24 kDa,
and 34 kDa) resulting from alternative initiations of mRNA translation [209]. There are
only three isoforms in mouse: 22 and 21 kDa high molecular weight (HMW) isoforms, and
one 18 kDa low molecular weight (LMW) isoform [210].
FGFs have a core region of around 120–140 amino acids forming 12 antiparallel β-
strands (β1–β12). A heparan sulphate proteoglycan binding site involves the β1–β2 loop
and parts of the region spanning β10 and β12. The core region is flanked by amino and
carboxyl termini [211].
• Receptors and signal transduction
The 18 secreted FGFs can bind to four Tyr kinase receptors (FGFR1–FGFR4). These
receptors, which share 46% sequence identity, have three extracellular immunoglobulin-like
domains (IgI, IgII, and IgIII), a single transmembrane domain, and a cytoplasmic Tyr kinase
domain [212]. FGFRs are expressed in different areas of the brain. For example, FGFR1
is widely expressed in the hippocampus and in various parts of the cortex, while FGFR4
is mainly found in the medial habenular nucleus. Both FGFR1 and FGFR4 are primarily
neuronal, whereas oligodendrocytes and astrocytes express FGFR2 and FGFR3 [213–215].
Upon binding of two FGF ligands and two heparan sulfate proteoglycans as cofactors,
the FGFR receptors dimerize and autophosphorylate, allowing the intracellular recruit-
ment of PLCγ1 and FRS2α (Figure 3). FRS2α activates the Ras/MAPK and PI3K/AKT
pathways [208], while PLCγ1 activates the Ca2+ /CAM and PKC pathways. The FGFR
kinase domain also initiates the signal transducer of activators of transcription (STAT)
pathways [208].
• Effect of FGF on CNS and AD hallmarks
FGFs, such as FGF-2, play an important role during brain development [216]. FGF-2
also controls the neurogenesis through its involvement in the differentiation of new neurons
in the adult dentate gyrus [217]. It is mainly synthesized by astrocytes in the CNS, and
by microglia and neurons in the CA2 region of the hippocampus [218]. FGF signaling,
especially the MAPK pathway, is crucial in the cell-fate switch from neurons to astrocytes
in the developing mouse cerebral cortex [191].
FGFs, such as FGF-2 and FGF-21, have been shown to be beneficial to treat AD
hallmarks (Table 1) [112,219]. While no difference was detected in the levels of LMW
FGF-2 between AD patients and age-matched healthy controls, the expression of HMW
FGF-2 isoforms was drastically decreased in AD patients [219]. Both FGF-2 HMW and
LMW isoforms can protect against Aβ1–42 -induced cytotoxicity in astrocytes through the
activation of the PI3K/AKT signaling pathway [111]. FGF-2 gene delivery by stereotaxic
hippocampal injection induces a decrease of Aβ through microglial activation in AD
transgenic APP.PS1 mice. In addition, it can restore spatial learning, hippocampal CA1 LTP,
and neurogenesis in APP.PS1 or J20 mice, two AD mice models [110].
FGF-2 can be administered systemically and cross the BBB to produce its effects. For
example, in 10.5-month-old female APP23 mice, a model of amyloid pathology, FGF-2
injected subcutaneously at 20-µg/kg per day for 3 weeks increases the number of astrocytes
and limits the expression of inflammatory mediators. It also reduces the generation of Aβ as
Int. J. Mol. Sci. 2021, 22, 6071 19 of 44

well as the phosphorylation of tau, while it restores the spatial memory [219]. The intranasal
administration of FGF-2/chitosan seems more effective to deliver the growth factor to
the brain in comparison to intravenous injection. It also induces a better improvement of
spatial memory in rat with learning impairment after co-injection of Aβ25–35 and ibotenic
acid [220]. These data suggest that intranasal administration of FGF-2 could have potential
application in AD.

3.3.2. Other Growth Factors

Other growth factors, notably ciliary neurotrophic factor (CNTF) (for a review, see [221])
and GDNF, are also interesting molecules because of their role in the progression of demen-
tia [153]. Insulin growth factors like IGF-1 have also been tested in the context of AD. Low
plasma levels of IGF-1 have been previously associated with decreased cognitive perfor-
mance [222,223]. However, a recent study reported that older males with high level of IGF-1
showed poor concurrent cognition. Furthermore, high levels of IGF-1 beyond a threshold
in middle-aged males are associated with a decline in future cognitive function [224].
The benefit of IGF-1 administration in the context of AD is also still under debate.
Some studies found that peripheral administration of IGF-1 (50 mg/kg/day) facilitates
the clearance of Aβ (Table 2) [225,226]. In contrast, IGF-1 delivery (50 mg/kg/day for
1 month) in 11-month-old Tg2576 mice has no beneficial effect on amyloid plaque load
or Aβ levels [227]. Furthermore, inhibition of IGF-1 signaling seems to decrease AD
hallmarks [228]. The administration of a potent inducer of circulating IGF-1 levels (MK-
677) also fails to delay AD progression in a randomized trial [229]. Further investigations
are therefore required to better understand the role played by IGF-1 and its signaling
in AD.
Int. J. Mol. Sci. 2021, 22, 6071 20 of 44

Table 2. Effect of the peptides derived from growth factors on CNS cells and their potential effect on Alzheimer’s disease.

Superfamily Peptide Sequence Experimental Conditions Effect on CNS Cells In Vitro or In Vivo Refs
Neurotrophin
Cells: mouse hippocampal HT-22 immortalized neurons and
Dimeric dipeptide: primary culture of embryonic rat hippocampal neurons (18 days old
embryos)
Treatment: peptide (10−5 –10−10 M) added 24 h before adding H2 O2 Strong neuroprotective properties at 10−8 M [230]
GK-2 β-turn loop L4
(1.5 mM) for 30 min or glutamate (5 mM) for 24 h
Incubation time: 4 h and 24 h

Dimeric dipeptides Cells: mouse hippocampal HT-22 immortalized neurons and rat Both GK-2 (10−8 M) and GK-6 (10−6 M):
GK-2 and pheochromocytoma PC12 ↑ Phosphorylation of TrkA
GK-6 β-turn loop L1 GK-6 (10−6 M): [231]
Treatment: peptide (10−5 –10−10 M) added 24 h before oxidative Exhibits slight neuroprotective properties
stress ↑ Differentiation (↑ neurite outgrowth in PC-12 at 7 days)
NGF N terminus
Cells: Rat PC12 pheochromocytoma cells ↑ Internalization of TrkA and p75NTR receptors
Linear peptide NGF(1-14)
SSSHPIFHRGEFSV-NH2 [232]
NGF Treatment: peptide at 50 µM or NGF (50 ng/mL) ↑ Proliferation of PC12 cells at 48 h
Dimeric peptide d-NGF(1-15)
Incubation time: 10 min to 72 h ↑ Differentiation (↑neurite total length at 72 h)

No effect on NGF (0.5 nM) binding to TrkA, supporting its specificity

Cyclic peptide Cells: p75NTR- and TrkA-NIH-3T3 cells and E17 fetal rat for p75NTR
cortical neurons ↓ Dose-dependent Aβ1–40 (0.5 nM) binding to p75NTR in rat cortical
neurons [233]
↓ Aβ1–40 (20 µM) signaling through p75NTR: ↓ c-jun mRNA and ↓
Treatment: Cyclic peptide (0–300 nM) for 30 min or 24 h and then
phosphorylation of cJUN
Aβ1–40 (0.5 nM, 25 nM or 20 µM) for 30 min
protects at 250 nM E17 neurons or 3T3 from Aβ1–40 (20 µM)
-induced toxicity
Animal: Mongrel male rats with bilaterally injection of GK-2 treatment can counteract the cognitive deficit in AD model
Dimeric dipeptide:
Streptozotocin 3 mg/kg into their cerebral ventricles (spatial memory impairment in Morris water maze) [234]
Treatment: GK-2 (0.5 mg/kg) or memantine (10 mg/kg) 4 h after
GK-2 Effect similar to memantine
the surgery and then once a day for 2 weeks
Animal: Ischemic stroke animal model; male Wistar rats (8–9 weeks)
Dimeric dipeptide: ↑ Hippocampal and striatum neurogenesis in rat cerebral ischemia
with intravascular thread occlusion of the middle cerebral artery [235]
Treatment: GK-2 (1 mg/kg, intraperitoneal); 6 or 24 h after surgery,
GK-2 ↓ Volume of the ischemic injury (60% when injected 6 h after surgery)
once a day for 6 days
Int. J. Mol. Sci. 2021, 22, 6071 21 of 44

Table 2. Cont.

Superfamily Peptide Sequence Experimental Conditions Effect on CNS Cells In Vitro or In Vivo Refs
Cyclic complex peptides derived from Cells: PC12 cells (clone 615) stably overexpressing TrkA,
loops L1 and L4 with or without NGF dorsal root ganglia (DRG) from 8-day-old chick embryos
N terminus and cerebellar granule neurons from 8-day-old Sprague In vitro:
Dawley rat pups Both NL1L4 and L1L4 (3 µM) have neurotrophic properties
NL1L4 Treatment: NL1L4 (3, 6 and 10 µM), L1L4 (50, 100 nM, 3, 6 ↑ DRG differentiation within 2 days like NGF
and 10 µM), and NGF (0.192 nM, control) L1L4 dose-dependent ↑ PC12 differentiation at 3 days (EC50
1 µM) [236]
↑ TrkA phosphorylation (pTrkA) in PC12 cells at 10 min
Incubation time: 10 min (TrkA activation); 2 weeks (DRG) (NL1L4 and L1L4 (3 µM): 57 and 80% of pTrkA level obtained
and 3 days (PC12) using NGF, respectively)
No effect on TrkB phosphorylation in cerebellar granule
neurons
L1L4 Animal: CCI model (adult male Sprague Dawley rats) In vivo:
treated by L1L4 (37.5 µg/µL) through intrathecal lumbar ↓ Neuropathic pain in CCI model (restores mechanical and
spinal catheter (1 µL/h for 7 days) thermal sensitivity)
Cells: NIH 3T3 cells transfected with TrkB receptor; ↑ TrkB phosphorylation at TrkB at Tyr 706 at 1 h
B-3 (Ac-SKKR-CONH2 ) mouse E18 primary No cytotoxic effect on cells at 5 days
↑ Neuronal differentiation (↑ b-III-tubulin,
hippocampal neurons anti-neurofilament-M, and NeuN) in E18 hippocampal
neurons at 5 days [237]
↑ BDNF synthesis induced by B-3 (0.1 and 1 µM) and B-5
Treatment: peptides (2 nM to 10 µM)
BDNF B-5 (Ac-IKRG-CONH2 ) (0.1 µM) in primary E18 hippocampal cells at 5 days
TrkB synthesis induced by B-3 and B-5 (1 µM) in NIH-3T3 at
Incubation time: 1 h; 2 and 5 days
5 days
Animal: male C57Bl/6 mice (chronic social defeat stress
GSB-106 ↑ Locomotion in CSDS mice
(CSDS))
[238]
Restores decreased synaptophysin level in hippocampus of
Treatment: GSB-106 0.1 mg/kg once a day, for 21 days
CSDS mice
Int. J. Mol. Sci. 2021, 22, 6071 22 of 44

Table 2. Cont.

Superfamily Peptide Sequence Experimental Conditions Effect on CNS Cells In Vitro or In Vivo Refs
BMP
↑ Neuronal differentiation (↑ neurite outgrowth; ↑
pBMP-9 Cells: SH-SY5Y cells
MAP-2, NSE. NeuN at 5 days).
Ac-
CGGKVGKACCVPTKLSPISVLYK- Treatment: peptides or BMP-9 (control) at 0.1 or 1 nM with or without SpBMP-9 ↑ differentiation in cholinergic phenotype. [239]
NH2 retinoic acid (RA) in serum-free medium (↑ acetylcholine, VAChT, ChAT) compared to BMP-9
SpBMP-9 or pBMP-9
BMP-9 Ac-CGGKVGKASSVPTKLSPISVLYK-
Incubation time: 1, 3, and 5 days. Adding RA ↑ peptide-induced differentiation
NH2
SpBMP-9 Cells: SH-SY5Y cells SpBMP-9 plus NGF or bFGF
↑ Neuronal differentiation (↑ neurite outgrowth, ↑
and NSpBMP-9 (negative peptide) Treatment: peptides at 0.1 nM with or without NGF (100 ng/mL) or
NSE expression) compared to growth factor alone
bFGF (FGF-2; 20 ng/mL) in serum-free medium [240]
↑ Neuronal differentiation in cholinergic phenotype.
Ac- (↑ VAChT vesicles located in the neurites) compared
CGGKVGKAGGVPTKLSPIGGLYK- with growth factor alone
NH2 Incubation time: 5 days. NSpBMP-9 has no effect
Cells: primary human glioblastoma cells (glioma stem cells
GBMP1a ↑ Astroglial differentiation (↑ GFAP protein
subpopulation)
BMP-2 (H-PFPLADHLNSTNHAIVQTLVNS- expression; ↑ S100) [241]
Treatment: 60 ng/mL GBMP1a
NH2 )
Incubation time: 5 days ↓ Cell proliferation
FGF
Cells: SH-SY5Y cell ↓ Glutamate-induced apoptosis via Akt activation
FGF-2 FK-18 FFFERLESNNYNTYSRK Treatment: FK18 at 10 µg/mL or bFGF at 100 ng/mL 2 h before, at the ↑ Bcl-2/Bax ratio [242]
same time, or 30 min after stimulation with glutamate (4–10 mM) ↓ Cleaved caspase-3
Int. J. Mol. Sci. 2021, 22, 6071 23 of 44

4. Peptides Derived from Growth Factors

To overcome the limitations encountered using native growth factors, alternative
strategies involving biologically active small peptides have been developed (Table 2), in
order to improve pharmacokinetic properties and BBB permeability, selectively activate
targeted signaling pathways (biased signaling), and decrease the side effects compared to
full-sized proteins [59,185]. Figure 4 summarizes the signaling pathways induced by the
peptides and their subsequent effect on neuronal differentiation, cholinergic phenotype,
and cell survival in vitro and/or in vivo.
Int. J. Mol. Sci. 2021, 22, 6071 24 of 44

Figure 4. Signaling pathways activated by peptides derived from growth factors and their effect in vitro and/or in vivo [232,239,243–245]. The figure was created using Servier Medical
Art (https://smart.servier.com; 30 April 2021).
Int. J. Mol. Sci. 2021, 22, 6071 25 of 44

4.1. Peptides Derived from Neurotrophins

4.1.1. NGF
• Peptides derived from mNGF L1-L4 loops
At first, NGF-derived peptides were designed based on conserved amino acid se-
quences that have a high degree of hydrophilicity and may correspond to the receptor bind-
ing sites [246]. Longo et al. have therefore identified three sequences: 26 TTATDIKGKEVTVLA
(region C), 64 VESGCRGIDSKHW (region A), and 99 WRFIRIDTA (region B) [246], corre-
sponding to potential active sites. Only the linear peptides derived from region C (C1
(ATDIKGKEVTV), C2 (DIKGKEVTV), and C5 (KGKE)) inhibited the neurite outgrowth
induced by NGF in sensory neurons. These antagonist peptides cannot block the binding of
NGF to its receptors [246]. However, Ibanez et al. found that the region C (28 ATDIKGKEV36 )
contains two lysines (K32 and K34) that are involved in NGF binding to p75NTR [247].
The resolution of the structure of mNGF explains that the lack of secondary structure
is why the linear peptides were unable to prevent NGF binding to the receptors. Indeed, X-
ray crystallographic analyses of mouse NGF showed that exposed sequences are organized
as three hydrophilic β-turn loops [248], later identified as L1, L2, and L4 loops, with an
additional exposed L3 loop (Figure 1) [68]. The L1 and L4 loops are known to be involved
in mNGF-receptor interaction [68]. Therefore, in addition to the region C corresponding to
the L1 loop (28 ATDIKGKEV36 ), three other sequences that are part of L2 (42 VNINNSVF49 ),
L3 (59 RASNPVESG67 ), and L4 (91 TTDEKQAAW99 ) were used to design linear or cyclic
peptides [249]. Only the small cyclic peptides mimicking the three-dimensional β-turn
conformation (C(30-35) CDIKGKEC; C(43-48) CNINNSVC; C(60-65) CASNPVEC; C(92-96)
CTDEKQC) were very potent antagonists of NGF. More importantly C(92-96) can bind
TrkA and inhibit the binding of NGF to the TrkA receptor [249,250].
Since the cyclization of the NGF-derived peptides mimicking β-turn loop structure
gave promising results to develop an NGF mimetic, Longo et al. developed several peptides
mainly based on the most efficient sequences 29 TDIKGKEV36 and KGKE (C5) [251]. To
obtain a stable oxidative peptide cyclization, penicillamine and cysteine were added at the
N- and C- (amide) extremities of the peptide, respectively. Among the designed peptides,
the cyclopeptide P7 (IPenKGKEVCT) has the greatest survival-promoting activity via
p75NTR receptors. More importantly, only the dimerization of P7 allows a neurotrophic
activity [251].
Other NGF dimeric mimetic peptides were developed based on the β-turn sequences
of loops L1 and L4, which most significantly protrude outward and must play a major role
in the interaction with the receptors [252]. Gudasheva et al. designed two dimeric dipep-
tides called GK-2 and GK-6 [230,231]. GK-2 is based on the L4 loop sequence 93 DEKQ96 .
To stabilize its conformation and limit its degradation by peptidase, Asp93 and Gln96 are
substituted by succinic acid residue and amide group, respectively. GK-6 is composed of
the dipeptide fragment of the first loop Gly33–Lys34, protected at its N- and C-terminus,
as described for GK-2 [231]. Both GK-2 and GK-6 were reported to mimic NGF activity
through their capacity to activate TrkA receptors in HT22 neurons (Table 2) [231]. However,
upon TrkA activation, GK-2 and GK-6 induce different signaling pathways (Figure 4) [243].
Like, NGF; GK-6 stimulates both the PI3K/AKT and MAPK/ERK1/2 pathways. In con-
trast, GK-2 only activates the PI3K/AKT pathway. GK-2 has a neuroprotective effect in
several models of oxidative stress [230]. GK-6 also exerts a neuroprotective effect. Unlike
GK-2, it induces the differentiation of rat PC12 pheochromocytoma cells, which requires
the activation of the MAPK/ERK1/2 pathway (Table 2) [243]. Furthermore, in contrast
to GK-6, GK-2 did not induce hyperalgesia, which is one of the primary adverse effects
of NGF [243]. Therefore, even if both peptides are agonists of TrkA, they induce a biased
signaling for a selective downstream pathway and different profiles of biological activity.
These are promising examples of how the design of peptides based on different binding
region of NGF is key in the development of pharmacological agents that target the desired
neuronal activity of NGF without the main side effects.
Int. J. Mol. Sci. 2021, 22, 6071 26 of 44

GTS-115 (bis(N-gamma-hydroxybutyryl-L-lysyl-L-histidine)), a peptide derived from

the β-turn sequence of loop L3, activates TrkA receptor and mediates its signal transduction
through the MAPK/ERK1/2 and PI3K/AKT pathways. It also shows a neuroprotective
activity on HT-22 cells cultured under an oxidative stress condition, but at a higher concen-
tration range (10–5 to 10–7 М) compared with GK-2 [252].
Because of their reported neuroprotective effects, several of these peptides were
also evaluated in vivo using animal models for various neurodegenerative diseases and
ischemic stroke (Table 2).
• Linear peptides derived from the mNGF N-terminal region
Given that the amino acid residues 4 to 13 of mNGF (especially His-4, His-8, Ile-6,
Phe-7, and Glu-11) play a crucial role in the interaction and activation of TrkA [253–255],
they were used to develop peptides derived from the mNGF N-terminal (Table 2).
NGF(1–14) is a linear peptide that encompasses the first 14 amino acid residues of the
human mNGF with the C-termini amidated to mimic the sequence within NGF [256,257]. It
triggers a slower, but longer lasting, activation and phosphorylation of TrkA in comparison
to NGF [257]. Interestingly, while NGF(1–14) is able to activate the PI3K/AKT pathway,
leading to GSK3β inactivation and phosphorylation of the transcription factor CREB, it
is unable to induce the phosphorylation of ERK1/2. As expected, since the MAPK/ERK
pathway is inactive, NGF(1−14) does not favor the differentiation of PC12 cells [257].
However, these results were in contradiction with those published by Pandini et al., who
observed an ERK1/2 activation in PC12 cells treated with NGF(1–14) [258]. The authors
suggested that the number of cell passages may have influenced the cell response. It was
also reported that the addition of Cu2+ , known to accumulate in AD brain [259], alters the
conformation of NGF(1–14) and significantly increases its proliferative effect [258].
NGF(1–14) is a monomer with no detectable propensity to dimerize [257]. Because
dimeric peptides are more efficient to mimic native NGF, d-NGF(1–15), a dimeric form of
NGF(1–14) peptide, was obtained via a cysteine-bridge linker of two monomeric units [232].
As shown for NGF(1–14), the secondary structure of d-NGF(1–15) is stabilized by Cu2+
ions; d-NGF(1–15) interacts with the d5 domain of TrkA and is a better TrkA activator than
NGF(1–14). It induces the activation of the MAPK/ERK1/2 and PI3K/AKT pathways,
triggers CREB phosphorylation, increases BDNF levels and secretion, and significantly
increases neurite outgrowth in rat PC12 cells (Table 2 and Figure 4) [232]. Thus, use of this
dimeric peptide is a promising strategy to restore the neurotrophin levels in neurodegener-
ative disease, such as AD.
• Peptides designed by combining sequences from mNGF loops L1 and L4 and the
N-terminal region
In order to increase the efficacy, more complex NGF-mimicking peptides, such as
NL1L4 and L1L4, were designed by combining sequences from well-known regions of
mNGF-TrkA binding sites. The NL1L4 peptide incorporates sequence residues of the
N-terminal region (His4 -Asp24 ), and residues from the L1 and L4 loops (Thr29 -Lys34 and
Asp92 -Gln95 ) that were cyclized to restrain their conformation flexibility and connected
with a linker TGA [236]. The L1L4 peptide was designed as NL1L4, but without the
N-terminal sequence. Both cyclic L1L4 and NL1L4 activate TrkA, but not TrkB. They also
induce differentiation of DRGs and PC12 cells, whereas the linear form of these peptides
did not, even at high concentration [236]. L1L4, which has the highest in vitro activity, is
also effective in reducing neuropathic pain in a chronic sciatic constriction injury (CCI)
model to an extent comparable to native NGF (Table 2) [236]. In addition, intrathecal
administration of this peptide does not cause the algesic effect of NGF [236], and is thus a
potential therapy for neuropathic pain and other brain disorders.
• Effect of NGF-derived peptides in the context of neurodegenerative diseases
Aβ has been reported to induce neuronal death by binding to p75NTR. Antagonis-
tic peptides have been designed to prevent this adverse effect of Aβ. A cyclic peptide
Int. J. Mol. Sci. 2021, 22, 6071 27 of 44

(CATDIKGAEC) was derived from mNGF-β hairpin loop L1 (residues 29-35), a region
interacting with p75NTR, but in which KGE was replaced by KGA, a motif shared by NGF
and Aβ [233]. This cyclic peptide inhibits NGF and Aβ1–40 binding to p75NTR, but not
to TrkA, and prevents the neuronal death induced by Aβ1–40 in E17 rat cortical neurons
(Table 2) [233].
Other NGF-derived peptides have shown a neuroprotective effect both in vitro and
in vivo. The dimeric peptide GK-2 (described in the subsection “Peptides derived from
mNGF L1-L4 loops”) had neuroprotective activities in several experimental models. It stim-
ulated neuroprotective and neurogenesis activities in vivo in a rat model of ischemic stroke
(Table 2) [235] and in several other experimental models of traumatic brain injury or degen-
erative diseases [59,260,261]. GK-2 counteracts the impaired cognitive functions in two AD
rat models: (1) a surgical one (transection of the septo-hippocampal pathway), resulting
in the development of cholinergic deficiency; and (2) a neurotoxic one (streptozotocin),
reproducing the main pathological hallmarks (Aβ accumulation and tau phosphorylation)
(Table 2) [234]. Importantly, GK-2 systemic administration, unlike the native NGF, did
not cause hyperalgesia and weight loss in these in vivo experiments [243]. These results
suggest that GK-2 may be a promising molecule to prevent the development of AD [234].
Through their capacity to target specific receptors and to selectively activate a subset
of signaling pathways, NGF-derived peptides can favor neuroprotective and neurogenera-
tion activities. These characteristics make these molecules very promising tools to fight
neurodegenerative diseases. However, a lot of work remains to better understand the effect
of such peptides on the complex AD pathogenesis.

4.1.2. BDNF
• Linear peptides derived from mBDNF
Using neutralizing antibodies directed to identify active sites of mBDNF, five different
linear tetrapeptides were designed (peptides B-1 to B-5). B-3, B-4, and B-5 peptides exert
neurogenic and neurotrophic effects in mouse hippocampal neuronal cell culture. Both B-5
and B-3 were found to work as partial agonists and antagonists for TrkB activation, and
also to induce the expression of TrkB and BDNF (Table 2) [237]. HNgfEE is another short
peptide derived from the NGF sequence that shares similarities with the BDNF sequence.
When conjugated to the surface of polymersome nanoparticles, this peptide can bind and
activate the TrkB receptor in vitro [262]. However, to date the efficiency of these peptides
have not been evaluated in vivo.
• Cyclic dimeric peptides derived from mBDNF loops L2 and L4
The cyclic peptides derived from BDNF were designed based on the X-ray crystal-
lographic data obtained for mouse NGF and a BDNF/NT3 heterodimer [263], revealing
the β-hairpin loop (L1-L4) regions in the BDNF primary sequence. In addition, specific
site-directed mutagenesis and chimeric proteins (NGF with the L2 region of BDNF) showed
that amino acid residues in the L2 loop are involved in the interaction with TrkB re-
ceptors [264,265]. Based on these information, four conformationally constrained cyclic
peptides of various size and derived from the L2 loop were synthesized (L2-12, L2-10, L2-8,
and L2-6). These peptides act as competitive antagonists of BDNF for TrkB. However, they
have no survival-promoting activity [263].
Bicyclic dimeric peptides (disulfide-linked and amide-linked dimers) were then de-
signed based on the L2-8 sequence (e.g., (H-CVCVSKGQLC-OH)2 ) in order to obtain
potent peptides mimetic of BDNF. These peptides behave as partial agonists, promoting the
survival (around 29% of the maximal survival effect of BDNF) of embryonic chick dorsal
root ganglion sensory neurons. To improve the potency/efficacy of these compounds,
tricyclic dimeric peptides (hybrids of the disulfide-linked and amide-linked dimers) were
also designed to reduce conformational freedom and potentially favor the orientation of
the two monomeric units for receptor dimerization. Although still partial agonists, these
Int. J. Mol. Sci. 2021, 22, 6071 28 of 44

peptides were very potent in increasing neuronal survival (100- to 1000-fold more potent
than the bicyclic disulfide-linked dimers) [266].
Other mimetic peptides of BDNF were designed based on the p75NTR-binding tripep-
tide motif KKR available on loop L4 of BDNF. For example, Fletcher et al. used a cyclic
pentapeptide (cyclo-[dPAKKR]) that consisted of the KKR tripeptide constrained by a dPro-
Ala linker. Unlike, BDNF; cyclo-[dPAKKR] cannot activate TrkB (Figure 4). However, it acts
as a BDNF agonist favoring the survival of primary embryonic chick sensory neurons. Fur-
thermore, this peptide is highly resistant to proteolytic degradation by plasma in vitro [244].
An alkyl amide-substituted analogue of this peptide (cyclo-[dPK(alkyl amide)KKR]), which
may recruit the peptide to cellular membrane, was found to be over 60-fold more potent
than cyclo-[dPAKKR] [267].
Based on these results, a dimer dipeptide named GSB-106 was derived from the BDNF
loop L4 β-turn sequence D93 SKK96 , where Asp93 was replaced by a succinic acid residue,
and Lys96 was replaced by an amide group [245]. Surprisingly, GSB-106 activates TrkB
receptors as well as the downstream PI3K/AKT, and MAPK/ERK1/2 and PLCγ [268].
It was also recently reported that GSB-106 induces the phosphorylation of TrkB via a
transactivation mechanism partially dependent on Src kinases in neuroblastoma SH-SY5Y
cells. GSB-106 exerts a neuroprotective effect against glutamate toxicity on cells expressing
TrkB. It also promotes survival of serum-deprived SH-SY5Y cells through TrkB/PI3K/AKT
pathway activation, which inhibits apoptosis [268]. Therefore, GSB-106 mimics BDNF in
its prosurvival activity.
• Peptides combining different regions of mBDNF
Long peptides derived from loops L3 and L4 in BDNF, Betrofin 3 (RGIDKRHWNSQ)
and Betrofin 4 (SYVRALTMDSKKRIGWR), respectively, were synthesized as dendrimers
composed of four monomers coupled to a lysine backbone. Both peptides can bind p75NTR
and TrkB receptors and induce neurite outgrowth of primary cerebellar granule neu-
rons [269]. Despite their effect on neuronal differentiation, the molecular weight of these
dendrimers is high and may limit their delivery to the brain.
• Effect of BDNF-derived peptides in the context of brain trauma and diseases
There are few studies on the effect of the BDNF-derived peptides in the context
of AD. However, their uses as antidepressants or to improve neurologic outcomes after
brain trauma have been well documented [270,271]. For example, GSB-106 improves
neurologic outcomes via PI3K/AKT and MAPK/ERK1/2 pathway activation in rat stroke
model caused by transient middle cerebral artery occlusion [271]. Furthermore, GSB-106
administered intraperitoneally or orally exhibits antidepressant activity [270,272,273]. It
also restores hippocampal neuroplasticity in a mice depression model induced by a chronic
social defeat stress procedure (Table 2) [238]. GSB-106 has therefore successfully passed
preclinical studies as a potential antidepressant.

4.2. Peptides Derived from BMP

4.2.1. Peptides Derived from the Knuckle Epitope
Based on the previous work of Saito et al. on BMP-2 [274], our research team has
designed two peptides, pBMP-9 and SpBMP-9, derived from the knuckle epitope of BMP-
9 corresponding to the amino acid residues recognized by the Type II Ser/Thr kinase
receptor BMPRII [275,276]. Like BMP-9, both peptides can activate the Smad canonical and
PI3K/AKT pathways, and inhibit GSK3β, a well-known tau kinase (Figure 4) [239]. Both
pBMP-9 and SpBMP-9 favor the differentiation of human neuroblastoma SH-SY5Y cells
toward neurons better than BMP-9, with SpBMP-9 being the most effective to promote the
cholinergic phenotype (Table 2) [239]. These results might be explained by a difference in
pBMP-9 and SpBMP-9 affinity for BMPRII receptors.
Several studies have shown that BMP-9 can induce the synthesis of NGF both in vitro
and in vivo, or act in synergy with other growth factors such as FGF-2 to promote the
differentiation of cholinergic neurons [106,190,198]. We therefore verified whether SpBMP-
Int. J. Mol. Sci. 2021, 22, 6071 29 of 44

9 can act with several growth factors (FGF-2, EGF, IGF-2) and neurotrophin NGF to promote
cholinergic differentiation of SH-SY5Y cells [240]. Unlike its negative peptide NSpBMP-9,
SpBMP-9 can potentiate the effect of both bFGF and NGF on SH-SY5Y cell differentiation
toward the cholinergic phenotype. In contrast, there is no synergistic effect in terms of
neurite outgrowth for cells stimulated with SpBMP-9 combined with IGF-2 or EGF [240].
These results showed that SpBMP-9 may be a promising molecule to treat AD by increasing
the cholinergic phenotype in combination with other growth factors and inhibiting GSK3β.
However, such small peptides must be protected to be delivered to the brain. SpBMP-9
was successfully encapsulated into composite nanoparticles made of alginate and chitosan
for its intranasal delivery. SpBMP-9 released from the nanoparticles was still biologically
active [277].
However, the evaluation of SpBMP-90 s efficiency to treat AD hallmarks first requires
several in vivo studies using appropriate AD mice models.

4.2.2. Peptide Derived from the Wrist Epitope

GBMP1a was designed based on the BMP-2 wrist epitope (residues 48–69) that
can bind ALK-3 [241]. GBMP1a activates, although to a lesser extent than BMP-2, the
Smad1/5/8 pathway in primary human brain tumor cells (glioblastoma). GBMP1a also
limits the ability of glioma stem cells to self-renew, but favors their astroglial differentiation
(Table 2) [241]. Even though the role played by astrocytes in neuroinflammation and human
AD brain is still poorly understood, a peptide inducing astroglial differentiation may be of
interest [278].

4.3. Peptides Derived from FGF and Other Factors

4.3.1. FGF-2
• Peptide derived from FGF-2
Baird et al. have analyzed the functional domains in the primary sequence of FGF-2
responsible for heparin binding. Among 25 fragments, two interesting sequences have
been identified: FGF (24-68) and FGF-2 (93-120). Both peptides can inhibit FGF-2 binding
to its receptors on BHK cells. However, the shorter peptide FGF (106-115) is 10- to 100-
fold more potent [279]. Furthermore, FK18, a peptide corresponding to the sequence
FGF-2 (93-110), shows neuroprotective effects against excitotoxic injury [242] and has
no toxic effect in vivo after its intravitreal administration. [280] (Table 2). The dimeric
FGF2-FGFR1c structure has also revealed various FGF-2 β loop–strand regions acting as
FGFR1 interaction sites [281]. This information was used to design different mimetic FGF-2
peptides (canofin1, canofin2, and canofin3) that were produced as tetrameric dendrimers
coupled to a three-lysine backbone [282]. All three canofins bind to FGFR1 with a lower
affinity than FGF-2. However, they induce neuronal differentiation, as shown by neurite
outgrowth from rat cerebellar granule neurons, and protect differentiated neurons from
apoptosis [282].
Because of their neuroprotective properties and neuronal differentiation effect, such
peptides may be interesting molecules to fight degenerative disease.

4.3.2. Other Growth Factors

• Peptides derived from IGF
A short tripeptide GPE derived from IGF-1 gave promising results as neuroprotective
molecule both in vitro and in vivo using experimental models of neurodegeneration and
brain trauma [283,284]. GPE is naturally released after the N-terminal cleavage of IGF-1 in
the brain [285]. The synthetic GPE peptide increases the acetylcholine release in rat cortical
brain slice in culture [286], and prevents the neuronal death in the hippocampus injured
by NMDA in vitro [287]. It can cross the BBB upon its intraperitoneal administration, and
reduces neuronal loss in the hippocampus after hypoxic–ischemic injury in adult rats [284].
To improve its pharmacokinetic, GPE was modified by adding an α-lipoic acid (LA-
GPE, R-α-Lipoyl-GPE dimethyl ester). Both GPE and LA-GPE prevent the death of SH-
Int. J. Mol. Sci. 2021, 22, 6071 30 of 44

SY5Y cells induced by Aβ1–42 in vitro. GPE-LA also reduces Aβ-induced AChE activity and
oxidative stress [288]. To increase its stability in the blood and reduce its degradation by
proteases, the amide bonds in GPE was replaced with an aminomethylene unit ψ[CH2 NH]
at Gly-Pro (GPE3), Pro-Glu (GPE1), or at both junctions (GPE2). As expected, GPE2 was
more stable than GPE1 and GPE3, with half-lives of 11.8 h, 4.5 h, and 6.6 h, respectively.
However, GPE3 had the best neuroprotective properties [289].
The GPE-modified peptides can block the effect of Aβ1–42 , limiting inflammation
and oxidative stress in vitro. They may therefore be considered for future application in
neurodegenerative diseases such as AD.
• Peptides derived from CNTF
CNTF is well known for its neuroprotective effect [221]. Two peptides, P6 and P021,
were derived from the biologically active region of human CNTF (amino acid residues
146–156) [290]. The peptide P6 is very stable over time, with a plasma half-life of over 6 h as
compared to 3 min for CNTF. It can also cross the BBB [291]. Both P6 and P021 gave promis-
ing results in the context of AD in several mice models [292–294]. The intraperitoneal
administration of P6 for six weeks in 6–7-month-old 3xTg-AD mice (prior to Aβ plaque
and neurofibrillary tangle formation) limits the impairment in spatial memory [292,293].
It potentiates the neurogenesis in APP transgenic (Tg) mice by increasing cell prolifera-
tion [294]. In the same way, P021 enhances the proliferation and differentiation of adult
hippocampal progenitors and improves cognition in C57Bl/6 mice and aged rats, favoring
the synthesis of BDNF [295,296]. Therefore, these peptides derived from CNTF are also
promising molecules to fight AD hallmarks.
In summary, the peptides derived from growth factors not only successfully mimic
the receptor binding sites, but also initiate specific signaling pathways such as PI3K/AKT,
MAPK/ERK1/2, and canonical Smad1/5/8 cascades involved in neuroprotective activity
(GK-2, FK-18), neurogenesis (GK-2), and cholinergic differentiation (SpBMP-9, pBMP-9).
Interestingly, some of them such as dNGF(1-15) and B-3/B-5 also promote the synthesis of
BDNF and the expression of its receptors, while others (GK-2; P06 and P021) counteract
the impaired cognitive functions in AD mice models without side effects. Furthermore,
peptides like GK-2 did not induce hyperalgesia, which is one of the primary adverse effects
of the native NGF protein. However, the side effects of peptides derived from growth
factors such as pBMP-9 and SpBMP-9 are still poorly known and require further studies.

5. Conclusions
Finding a therapy for AD disease is one of the greatest challenges for modern medicine,
since it is a multifactorial disease. Currently, major clinical trials are mainly focusing on
Aβ hypothesis components, but have been largely unsuccessful. None of the available
drugs protects against the loss of neurons, a hallmark in AD pathogenesis. In this regard,
the exogenous administration of peptides derived from growth factors is an attractive
therapeutic approach, given their roles in proliferation, differentiation, plasticity, and sur-
vival of neuronal cells. The strong supportive preclinical data in primary cells and animal
models indicate the potential/viability of this strategy for AD treatment. Several short
peptides derived from neurotrophins (NGF, BDNF), members of the TGF beta superfamily
(BMP), and FGF have been developed or are under development to replace the deficient or
dysregulated growth factor in AD. An advantage of these peptides is that their structure
can be constrained (or designed) to better interact with the growth factor receptors and to
activate a specific downstream pathway such as MAPK/ERK versus PI3K/AKT to favor
a subsequent behavior like neuronal survival and/or differentiation. It also offers the
opportunity to develop new therapeutic strategies by combining some of these peptides
together or with other available treatment for a multimodal approach. Blood stability
and pharmacokinetic properties of these peptides can also be improved by chemical mod-
ification. Their small size facilitates the penetration of the BBB to reach neuronal cells.
However, systemic administration of these peptides could lead to serious peripheral side
effects by acting on receptors in other tissues. Intranasal delivery or encapsulated cell
Int. J. Mol. Sci. 2021, 22, 6071 31 of 44

biodelivery methods could help to overcome this limitation. Interestingly, if started early
in the progression of the disease, this treatment could alter the relentless cognitive decline.
However, future studies are required to better understand and improve the efficacy of
these promising molecules in the context of AD pathogenesis.

Author Contributions: S.G., J.J. and C.L.-B. wrote the draft of the manuscript and designed the tables
under the supervision of M.P., C.L. and N.F.; C.L. and N.F. designed the figures and contributed to
the writing and editing of the manuscript. All authors have read and agreed to the published version
of the manuscript.
Funding: The APC was funded by the IPS program (structuring project).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

AAV2-NGF Adenoviral vector to deliver NGF

ActR-1A Type 1A activin receptor
ActRIIA Type II activin receptor
ActRIIB Type IIB activin receptor
AD Alzheimer’s disease
ADAM17 A disintegrin and metalloproteinase 17
ALK Activin receptor-like kinases receptor
AMH/MIS Anti-Müllerian hormone/Müllerian inhibiting substance
AMHRII Anti-Mullerian hormone receptor type II
AMPA Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
APOE Apolipoprotein E
APOE4 Apolipoprotein E4
APP Amyloid-β precursor protein
AVVS2-NGF Adeno-associated virus serotype 2 delivering NGF
Aβ Amyloid-β
BAMBI BMP and activin membrane-bound inhibitor
BBB Blood–brain barrier
BDNF Brain-derived neurotrophic factor (mature form: mBDNF)
BFCNs Cholinergic neurons of the basal forebrain
BMP Bone morphogenetic protein (mature form)
BMPR-1A Type 1A BMP receptor
BMPR-1B Type 1B BMP receptor
BMPRII Type II BMP receptor
CAM Calmodulin kinase
CDC42 Cell division control protein 42 homolog
ChAT Acetylcholine synthesis enzyme
CNS Central nervous system
CNTF Ciliary neurotrophic factor
CR Cysteine clusters
CREB cAMP response element-binding protein
DAG Diacylglycerol
DMSO Dimethyl sulfoxide
dpp Drosophila decapentaplegic
ERK1/2 Extracellular signal-regulated kinase
FDA Food and Drug Administration
FGF Fibroblast growth factor
FGFR Fibroblast growth factor receptor
Int. J. Mol. Sci. 2021, 22, 6071 32 of 44

FRS2 Fibroblast growth factor receptor substrate 2

Gab1 Grb2-associated binder-1
GDF Growth differentiation factors
GDNF Glial derived neurotrophic factor
GFAP Glial fibrillary acidic protein
GPCRs G-protein-coupled receptors
Grb2 Growth factor receptor-bound protein 2
GSK3β Glycogen synthase kinase-3-β
GWAS Genome-wide association
HMW High molecular weight
Ig-C2 Immunoglobulin-like C2 type domains
IGF Insulin-like growth factor
IP3 Inositol 1,4,5-trisphosphate
I-Smad Inhibitory Smad: Smad6/7
JNK cJun N-terminal kinase
Lhx8 LIM homeobox 8
LMW Low molecular weight
LOAD Late-onset Alzheimer’s disease
LRR1-3 Leucine-rich 24-residue motifs
LTP Long-term potentiation
MAGE Melanoma-associated antigen
MAP-2 Microtubule associated protein 2
MAPK Mitogen-activated protein kinase
MMP-9 Matric metalloprotease
NeuN Neuronal nuclear protein
NF-kB Nuclear factor kB
NG2 Neuron-glial antigen 2
NGF Nerve growth factor (mature form: mNGF)
NMDA N-methyl-D-aspartate
NMDAR NMDA receptor
NRAGE Neurotrophin receptor-interacting MAGE protein
NSE Neuron specific enolase
NT-3 Neurotrophin-3
NT-4/5 Neurotrophin-4/5
p75NTR p75 neurotrophin receptor
PI3K/AKT Phosphoinositide 3-kinase/protein kinase B
PIP2 Phosphatidylinositol 4,5-bisphosphate
PKC Protein kinase C
PLCγ Phospholipase Cγ
PPM1A Protein phosphatase magnesium-dependent 1A
RAF Rapidly accelerated fibrosarcoma
RhoGDI1 RhoGDP dissociation inhibitor 1
Shc Src homology 2 domain containing
Smad Small mothers against decapentaplegic
SOS Salt overly sensitive
STAT Signal transducer of activators of transcription
TAB1/2/3 TAK1-binding protein 1/2/3
TAK1 Transforming growth factor β-activated kinase 1
TF Transcription factor
Tg Transgenic
TGF-β Transforming growth factor-β
TRAF TNF receptor associated factor
TREM2 Triggering receptor expressed on myeloid cells 2
Trk Tropomyosin receptor kinase
Trk-FL Trk full length
VAChT Vericular acetylcholine transporter
WHO World Health Organization
WT Wild type
XIAP X-linked inhibitor of apoptosis
Int. J. Mol. Sci. 2021, 22, 6071 33 of 44

References
1. Alzheimer’s Association Report. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021, 17, 327–406. [CrossRef]
[PubMed]
2. Prince, M.; Comas-Herrera, A.; Knapp, M.; Guerchet, M.; Karagiannidou, M. World Alzheimer Report 2016; Alzheimer’s Disease
International (ADI): London, UK, 2016.
3. Calderon-Garciduenas, A.L.; Duyckaerts, C. Alzheimer disease. Handb. Clin. Neurol. 2017, 145, 325–337. [CrossRef] [PubMed]
4. Bekdash, R.A. The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease. Int. J. Mol. Sci.
2021, 22, 1273. [CrossRef] [PubMed]
5. Mitra, S.; Behbahani, H.; Eriksdotter, M. Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF. Front.
Neurosci. 2019, 13, 38. [CrossRef]
6. Bartus, R.T.; Dean, R.L., 3rd; Beer, B.; Lippa, A.S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982, 217,
408–414. [CrossRef]
7. DeTure, M.A.; Dickson, D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019, 14, 32. [CrossRef]
8. Nunan, J.; Small, D.H. Regulation of APP cleavage by α-, β- and γ-secretases. FEBS Lett. 2000, 483, 6–10. [CrossRef]
9. Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 2010, 7,
656–664. [CrossRef]
10. Reddy, P.H. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in
Alzheimer’s disease. Brain Res. 2011, 1415, 136–148. [CrossRef]
11. Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016, 8, 595–608. [CrossRef]
12. Zhao, J.; Liu, X.; Xia, W.; Zhang, Y.; Wang, C. Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease. Front. Mol.
Neurosci. 2020, 13, 137. [CrossRef]
13. Jonsson, T.; Atwal, J.K.; Steinberg, S.; Snaedal, J.; Jonsson, P.V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney,
J.; et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 2012, 488, 96–99.
[CrossRef]
14. Bekris, L.M.; Yu, C.E.; Bird, T.D.; Tsuang, D.W. Genetics of Alzheimer disease. J. Geriatr. Psychiatry Neurol. 2010, 23, 213–227.
[CrossRef]
15. Corder, E.H.; Saunders, A.M.; Strittmatter, W.J.; Schmechel, D.E.; Gaskell, P.C.; Small, G.W.; Roses, A.D.; Haines, J.L.; Pericak-
Vance, M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993,
261, 921–923. [CrossRef]
16. Zheng, H.; Cheng, B.; Li, Y.; Li, X.; Chen, X.; Zhang, Y.W. TREM2 in Alzheimer’s Disease: Microglial Survival and Energy
Metabolism. Front. Aging Neurosci. 2018, 10, 395. [CrossRef] [PubMed]
17. Serrano-Pozo, A.; Das, S.; Hyman, B.T. APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic
approaches. Lancet Neurol. 2021, 20, 68–80. [CrossRef]
18. Kloske, C.M.; Wilcock, D.M. The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease.
Front. Immunol. 2020, 11, 754. [CrossRef]
19. Husain, M.A.; Laurent, B.; Plourde, M. APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeu-
tics. Front. Neurosci. 2021, 15, 630502. [CrossRef]
20. Van Cauwenberghe, C.; Van Broeckhoven, C.; Sleegers, K. The genetic landscape of Alzheimer disease: Clinical implications and
perspectives. Genet. Med. 2016, 18, 421–430. [CrossRef]
21. Vidal, C.; Zhang, L. An Analysis of the Neurological and Molecular Alterations Underlying the Pathogenesis of Alzheimer’s
Disease. Cells 2021, 10, 546. [CrossRef]
22. Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M.
Alzheimer’s disease. Lancet 2021, 397, 1577–1590. [CrossRef]
23. Shaikh, S.; Verma, A.; Siddiqui, S.; Ahmad, S.S.; Rizvi, S.M.; Shakil, S.; Biswas, D.; Singh, D.; Siddiqui, M.H.; Shakil, S.; et al.
Current acetylcholinesterase-inhibitors: A neuroinformatics perspective. CNS Neurol. Disord. Drug. Targets 2014, 13, 391–401.
[CrossRef] [PubMed]
24. Liu, J.; Chang, L.; Song, Y.; Li, H.; Wu, Y. The Role of NMDA Receptors in Alzheimer’s Disease. Front. Neurosci. 2019, 13, 43.
[CrossRef]
25. Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the Cholinergic System. Curr.
Neuropharmacol. 2016, 14, 101–115. [CrossRef]
26. Deardorff, W.J.; Feen, E.; Grossberg, G.T. The Use of Cholinesterase Inhibitors Across All Stages of Alzheimer’s Disease. Drugs
Aging 2015, 32, 537–547. [CrossRef]
27. Kang, Y.J.; Diep, Y.N.; Tran, M.; Cho, H. Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease. Int. J.
Mol. Sci. 2020, 21, 9591. [CrossRef]
28. Doody, R.S.; Raman, R.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; He, F.; Sun, X.; Thomas, R.G.; et al. A phase 3
trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 2013, 369, 341–350. [CrossRef]
29. De Strooper, B. Lessons from a failed gamma-secretase Alzheimer trial. Cell 2014, 159, 721–726. [CrossRef]
30. Egan, M.F.; Kost, J.; Voss, T.; Mukai, Y.; Aisen, P.S.; Cummings, J.L.; Tariot, P.N.; Vellas, B.; van Dyck, C.H.; Boada, M.; et al.
Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease. N. Engl. J. Med. 2019, 380, 1408–1420. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 34 of 44

31. Caselli, R.J.; Knopman, D.S.; Bu, G. An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer’s disease
pathogenesis: The role of APP homeostasis. Alzheimers Dement. 2020, 16, 1582–1590. [CrossRef]
32. Mintun, M.A.; Lo, A.C.; Duggan Evans, C.; Wessels, A.M.; Ardayfio, P.A.; Andersen, S.W.; Shcherbinin, S.; Sparks, J.; Sims, J.R.;
Brys, M.; et al. Donanemab in Early Alzheimer’s Disease. N. Engl. J. Med. 2021, 384, 1691–1704. [CrossRef] [PubMed]
33. Jadhav, S.; Avila, J.; Scholl, M.; Kovacs, G.G.; Kovari, E.; Skrabana, R.; Evans, L.D.; Kontsekova, E.; Malawska, B.; de Silva, R.; et al.
A walk through tau therapeutic strategies. Acta Neuropathol. Commun. 2019, 7, 22. [CrossRef] [PubMed]
34. Ngandu, T.; Lehtisalo, J.; Solomon, A.; Levälahti, E.; Ahtiluoto, S.; Antikainen, R.; Bäckman, L.; Hänninen, T.; Jula, A.; Laatikainen,
T.; et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control
to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial. Lancet 2015, 385, 2255–2263.
[CrossRef]
35. Hampel, H.; Caraci, F.; Cuello, A.C.; Caruso, G.; Nistico, R.; Corbo, M.; Baldacci, F.; Toschi, N.; Garaci, F.; Chiesa, P.A.; et al. A
Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer’s Disease. Front. Immunol. 2020, 11, 456.
[CrossRef] [PubMed]
36. Chun, H.; Im, H.; Kang, Y.J.; Kim, Y.; Shin, J.H.; Won, W.; Lim, J.; Ju, Y.; Park, Y.M.; Kim, S.; et al. Severe reactive astrocytes
precipitate pathological hallmarks of Alzheimer’s disease via H2O2(-) production. Nat. Neurosci. 2020, 23, 1555–1566. [CrossRef]
37. Yang, A.; Kantor, B.; Chiba-Falek, O. APOE: The New Frontier in the Development of a Therapeutic Target towards Precision
Medicine in Late-Onset Alzheimer’s. Int. J. Mol. Sci. 2021, 22, 1244. [CrossRef]
38. Allen, S.J.; Watson, J.J.; Dawbarn, D. The neurotrophins and their role in Alzheimer’s disease. Curr. Neuropharmacol. 2011, 9,
559–573. [CrossRef]
39. Zhang, L.; Fang, Y.; Lian, Y.; Chen, Y.; Wu, T.; Zheng, Y.; Zong, H.; Sun, L.; Zhang, R.; Wang, Z.; et al. Brain-derived neurotrophic
factor ameliorates learning deficits in a rat model of Alzheimer’s disease induced by abeta1-42. PLoS ONE 2015, 10, e0122415.
[CrossRef]
40. De Rosa, R.; Garcia, A.A.; Braschi, C.; Capsoni, S.; Maffei, L.; Berardi, N.; Cattaneo, A. Intranasal administration of nerve growth
factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. USA 2005, 102,
3811–3816. [CrossRef]
41. Rafii, M.S.; Tuszynski, M.H.; Thomas, R.G.; Barba, D.; Brewer, J.B.; Rissman, R.A.; Siffert, J.; Aisen, P.S.; Team, A.N.S. Adeno-
Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial.
JAMA Neurol. 2018, 75, 834–841. [CrossRef]
42. Allen, S.J.; Watson, J.J.; Shoemark, D.K.; Barua, N.U.; Patel, N.K. GDNF, NGF and BDNF as therapeutic options for neurodegener-
ation. Pharmacol. Ther. 2013, 138, 155–175. [CrossRef]
43. Hallböök, F. Evolution of the vertebrate neurotrophin and Trk receptor gene families. Curr. Opin. Neurobiol. 1999, 9, 616–621.
[CrossRef]
44. Aloe, L. Rita Levi-Montalcini: The discovery of nerve growth factor and modern neurobiology. Trends Cell Biol. 2004, 14, 395–399.
[CrossRef]
45. Aid, T.; Kazantseva, A.; Piirsoo, M.; Palm, K.; Timmusk, T. Mouse and rat BDNF gene structure and expression revisited. J.
Neurosci. Res. 2007, 85, 525–535. [CrossRef]
46. Pruunsild, P.; Kazantseva, A.; Aid, T.; Palm, K.; Timmusk, T. Dissecting the human BDNF locus: Bidirectional transcription,
complex splicing, and multiple promoters. Genomics 2007, 90, 397–406. [CrossRef]
47. Baj, G.; Enrico, T. BDNF splice variants from the second promoter cluster support cell survival of differentiated neuroblastoma
upon cytotoxic stress. J. Cell Sci. 2009, 122, 36–43. [CrossRef]
48. Chiaruttini, C.; Sonego, M.; Baj, G.; Simonato, M.; Tongiorgi, E. BDNF mRNA splice variants display activity-dependent targeting
to distinct hippocampal laminae. Mol. Cell Neurosci. 2008, 37, 11–19. [CrossRef]
49. Tuvikene, J.; Pruunsild, P.; Orav, E.; Esvald, E.E.; Timmusk, T. AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop
in Cortical Neurons. J. Neurosci. 2016, 36, 1290–1305. [CrossRef]
50. Hong, E.J.; McCord, A.E.; Greenberg, M.E. A biological function for the neuronal activity-dependent component of Bdnf
transcription in the development of cortical inhibition. Neuron 2008, 60, 610–624. [CrossRef]
51. Lubin, F.D.; Roth, T.L.; Sweatt, J.D. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J.
Neurosci. 2008, 28, 10576–10586. [CrossRef]
52. Bruno, M.A.; Cuello, A.C. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor,
and its degradation by a protease cascade. Proc. Natl. Acad. Sci. USA 2006, 103, 6735–6740. [CrossRef] [PubMed]
53. Allard, S.; Jacobs, M.L.; Do Carmo, S.; Cuello, A.C. Compromise of cortical proNGF maturation causes selective retrograde
atrophy in cholinergic nucleus basalis neurons. Neurobiol. Aging 2018, 67, 10–20. [CrossRef] [PubMed]
54. Iulita, M.F.; Bistue Millon, M.B.; Pentz, R.; Aguilar, L.F.; Do Carmo, S.; Allard, S.; Michalski, B.; Wilson, E.N.; Ducatenzeiler, A.;
Bruno, M.A.; et al. Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer’s disease.
Neurobiol. Dis. 2017, 108, 307–323. [CrossRef] [PubMed]
55. Cuello, A.C.; Pentz, R.; Hall, H. The Brain NGF Metabolic Pathway in Health and in Alzheimer’s Pathology. Front. Neurosci. 2019,
13, 62. [CrossRef]
56. Ullrich, A.; Gray, A.; Berman, C.; Dull, T.J. Human β-nerve growth factor gene sequence highly homologous to that of mouse.
Nature 1983, 303, 821–825. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 35 of 44

57. Lewin, G.R.; Barde, Y.A. Physiology of the neurotrophins. Annu. Rev. Neurosci. 1996, 19, 289–317. [CrossRef]
58. McDonald, N.Q.; Lapatto, R.; Rust, J.M.; Gunning, J.; Wlodawer, A.; Blundell, T.L. New protein fold revealed by a 2.3-Å resolution
crystal structure of nerve growth factor. Nature 1991, 354, 411–414. [CrossRef]
59. Gudasheva, T.A.; Povarnina, P.Y.; Tarasiuk, A.V.; Seredenin, S.B. Low-molecular mimetics of nerve growth factor and brain-
derived neurotrophic factor: Design and pharmacological properties. Med. Res. Rev. 2020. [CrossRef]
60. Mcdonald, N.Q.; Lapatto, R.; Murray-Rust, J.; Gunning, J.; Wlodawer, A.; Blundell, T.L. New protein fold revealed by a 2.3
angstrom resolution crystal structure of nerve growth factor. Nature 1993. [CrossRef]
61. He, X.; Garcia, K.C. Structure of the extracellular segment of human TRKA in complex with nerve growth factor. 2006. [CrossRef]
62. Wehrman, T.; He, X.; Raab, B.; Dukipatti, A.; Blau, H.; Garcia, K.C. Structural and mechanistic insights into nerve growth factor
interactions with the TrkA and p75 receptors. Neuron 2007, 53, 25–38. [CrossRef]
63. Huang, E.J.; Reichardt, L.F. Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 2003, 72, 609–642. [CrossRef]
64. Nykjaer, A.; Lee, R.; Teng, K.K.; Jansen, P.; Madsen, P.; Nielsen, M.S.; Jacobsen, C.; Kliemannel, M.; Schwarz, E.; Willnow, T.E.;
et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 2004, 427, 843–848. [CrossRef]
65. Yan, Q.; Radeke, M.J.; Matheson, C.R.; Talvenheimo, J.; Welcher, A.A.; Felnstein, S.C. Immunocytochemical localization of TrkB in
the central nervous system of the adult rat. J. Comp. Neurol. 1997, 378, 135–157. [CrossRef]
66. Chao, M.V.; Hempstead, B.L. p75 and Trk: A two-receptor system. Trends Neurosci. 1995, 18, 321–326. [CrossRef]
67. Mahadeo, D.; Kaplan, L.; Chao, M.V.; Hempstead, B.L. High affinity nerve growth factor binding displays a faster rate of
association than p140trk binding. Implications for multi-subunit polypeptide receptors. J. Biol. Chem. 1994, 269, 6884–6891.
[CrossRef]
68. Wiesmann, C.; Ultsch, M.H.; Bass, S.H.; de Vos, A.M. Crystal structure of nerve growth factor in complex with the ligand-binding
domain of the TrkA receptor. Nature 1999, 401, 184–188. [CrossRef]
69. Barbacid, M. The Trk family of neurotrophin receptors. J. Neurobiol. 1994, 25, 1386–1403. [CrossRef]
70. Molloy, N.H.; Read, D.E.; Gorman, A.M. Nerve growth factor in cancer cell death and survival. Cancers 2011, 3, 510–530.
[CrossRef]
71. Meeker, R.B.; Williams, K.S. The p75 neurotrophin receptor: At the crossroad of neural repair and death. Neural. Regen. Res. 2015,
10, 721–725. [CrossRef]
72. Pramanik, S.; Sulistio, Y.A.; Heese, K. Neurotrophin Signaling and Stem Cells-Implications for Neurodegenerative Diseases and
Stem Cell Therapy. Mol. Neurobiol. 2017, 54, 7401–7459. [CrossRef] [PubMed]
73. Sasi, M.; Vignoli, B.; Canossa, M.; Blum, R. Neurobiology of local and intercellular BDNF signaling. Pflugers. Arch. 2017, 469,
593–610. [CrossRef]
74. Amidfar, M.; de Oliveira, J.; Kucharska, E.; Budni, J.; Kim, Y.K. The role of CREB and BDNF in neurobiology and treatment of
Alzheimer’s disease. Life Sci. 2020, 257, 118020. [CrossRef]
75. Colucci-D’Amato, L.; Speranza, L.; Volpicelli, F. Neurotrophic Factor, BDNF.; Physiological Functions and Therapeutic Potential
in Depression, Neurodegeneration and Brain Cancer. Int. J. Mol. Sci. 2020, 21, 7777. [CrossRef]
76. Notaras, M.; van den Buuse, M. Brain-Derived Neurotrophic Factor (BDNF): Novel Insights into Regulation and Genetic Variation.
Neuroscientist 2019, 25, 434–454. [CrossRef]
77. Tomioka, T.; Shimazaki, T.; Yamauchi, T.; Oki, T.; Ohgoh, M.; Okano, H. LIM homeobox 8 (Lhx8) is a key regulator of the
cholinergic neuronal function via a tropomyosin receptor kinase A (TrkA)-mediated positive feedback loop. J. Biol. Chem. 2014,
289, 1000–1010. [CrossRef]
78. Minichiello, L.; Calella, A.M.; Medina, D.L.; Bonhoeffer, T.; Klein, R.; Korte, M. Mechanism of TrkB-Mediated Hippocampal
Long-Term Potentiation. Neuron 2002, 36, 121–137. [CrossRef]
79. Lee, F.S.; Rajagopal, R.; Kim, A.H.; Chang, P.C.; Chao, M.V. Activation of Trk neurotrophin receptor signaling by pituitary
adenylate cyclase-activating polypeptides. J. Biol. Chem. 2002, 277, 9096–9102. [CrossRef]
80. Takei, N.; Torres, E.; Yuhara, A.; Jongsma, H.; Otto, C.; Korhonen, L.; Abiru, Y.; Skoglosa, Y.; Schutz, G.; Hatanaka, H.; et al.
Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and
in vivo: Comparison with effects of nerve growth factor. Eur. J. Neurosci. 2000, 12, 2273–2280. [CrossRef]
81. Ohira, K.; Kumanogoh, H.; Sahara, Y.; Homma, K.J.; Hirai, H.; Nakamura, S.; Hayashi, M. A truncated tropomyosin-related
kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J. Neurosci. 2005, 25, 1343–1353.
[CrossRef]
82. Ohira, K.; Homma, K.J.; Hirai, H.; Nakamura, S.; Hayashi, M. TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in
glioma cells. Biochem. Biophys. Res. Commun. 2006, 342, 867–874. [CrossRef] [PubMed]
83. Fenner, B.M. Truncated TrkB: Beyond a dominant negative receptor. Cytokine Growth. Factor Rev. 2012, 23, 15–24. [CrossRef]
[PubMed]
84. Cao, T.; Matyas, J.J.; Renn, C.L.; Faden, A.I.; Dorsey, S.G.; Wu, J. Function and Mechanisms of Truncated BDNF Receptor TrkB.T1
in Neuropathic Pain. Cells 2020, 9, 1194. [CrossRef] [PubMed]
85. Charalampopoulos, I.; Vicario, A.; Pediaditakis, I.; Gravanis, A.; Simi, A.; Ibanez, C.F. Genetic dissection of neurotrophin signaling
through the p75 neurotrophin receptor. Cell Rep. 2012, 2, 1563–1570. [CrossRef]
86. Kowianski, P.; Lietzau, G.; Czuba, E.; Waskow, M.; Steliga, A.; Morys, J. BDNF: A Key Factor with Multipotent Impact on Brain
Signaling and Synaptic Plasticity. Cell Mol. Neurobiol. 2018, 38, 579–593. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 36 of 44

87. Chen, Z.Y.; Ieraci, A.; Teng, H.; Dall, H.; Meng, C.X.; Herrera, D.G.; Nykjaer, A.; Hempstead, B.L.; Lee, F.S. Sortilin controls
intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J. Neurosci. 2005, 25, 6156–6166.
[CrossRef]
88. Counts, S.E.; Mufson, E.J. The Role of Nerve Growth Factor Receptors in Cholinergic Basal Forebrain Degeneration in Prodromal
Alzheimer Disease. J. Neuropathol. Exp. Neurol. 2005, 64, 263–272. [CrossRef]
89. Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.Y.; Lee, F.S.; et al. ProBDNF
induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 2005, 25, 5455–5463.
[CrossRef]
90. Almeida, R.D.; Manadas, B.J.; Melo, C.V.; Gomes, J.R.; Mendes, C.S.; Graos, M.M.; Carvalho, R.F.; Carvalho, A.P.; Duarte, C.B.
Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell
Death Differ. 2005, 12, 1329–1343. [CrossRef]
91. Leal, G.; Afonso, P.M.; Salazar, I.L.; Duarte, C.B. Regulation of hippocampal synaptic plasticity by BDNF. Brain Res. 2015, 1621,
82–101. [CrossRef]
92. Lärkfors, L.; Ebendal, T.; Whittemore, S.R.; Persson, H.; Hoffer, B.; Olson, L. Decreased level of nerve growth factor (NGF) and its
messenger RNA in the aged rat brain. Mol. Brain Res. 1987, 3, 55–60. [CrossRef]
93. Goedert, M.; Fine, A.; Hunt, S.P.; Ullrich, A. Nerve growth factor mRNA in peripheral and central rat tissues and in the human
central nervous system: Lesion effects in the rat brain and levels in Alzheimer’s disease. Mol. Brain Res. 1986, 1, 85–92. [CrossRef]
94. Solari, N.; Hangya, B. Cholinergic modulation of spatial learning, memory and navigation. Eur. J. Neurosci. 2018, 48, 2199–2230.
[CrossRef]
95. Gielow, M.R.; Zaborszky, L. The Input-Output Relationship of the Cholinergic Basal Forebrain. Cell Rep. 2017, 18, 1817–1830.
[CrossRef]
96. Cuello, A.C. Chapter 32: Trophic responses of forebrain cholinergic neurons: A discussion. In Progress in Brain Research; Cuello,
A.C., Ed.; Elsevier: Amsterdam, The Netherlands, 1993; pp. 265–277.
97. Berse, B.; Lopez-Coviella, I.; Blusztajn, J.K. Activation of TrkA by nerve growth factor upregulates expression of the cholinergic
gene locus but attenuates the response to ciliary neurotrophic growth factor. Biochem. J. 1999, 342 Pt 2, 301–308. [CrossRef]
98. Fagan, A.M.; Garber, M.; Barbacid, M.; Silos-Santiago, I.; Holtzman, D.M. A Role for TrkA during Maturation of Striatal and Basal
Forebrain Cholinergic NeuronsIn Vivo. J. Neurosci. 1997, 17, 7644–7654. [CrossRef]
99. Crowley, C.; Spencer, S.D.; Nishimura, M.C.; Chen, K.S.; Pitts-Meek, S.; Armaninl, M.P.; Ling, L.H.; McMahon, S.B.; Shelton, D.L.;
Levinson, A.D.; et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop
basal forebrain cholinergic neurons. Cell 1994, 76, 1001–1011. [CrossRef]
100. Eu, W.Z.; Chen, Y.J.; Chen, W.T.; Wu, K.Y.; Tsai, C.Y.; Cheng, S.J.; Carter, R.N.; Huang, G.J. The effect of nerve growth factor on
supporting spatial memory depends upon hippocampal cholinergic innervation. Transl. Psychiatry 2021, 11, 162. [CrossRef]
101. Chen, K.S.; Nishimura, M.C.; Armanini, M.P.; Crowley, C.; Spencer, S.D.; Phillips, H.S. Disruption of a Single Allele of the Nerve
Growth Factor Gene Results in Atrophy of Basal Forebrain Cholinergic Neurons and Memory Deficits. J. Neurosci. 1997, 17,
7288–7296. [CrossRef]
102. Allard, S.; Leon, W.C.; Pakavathkumar, P.; Bruno, M.A.; Ribeiro-da-Silva, A.; Cuello, A.C. Impact of the NGF maturation and
degradation pathway on the cortical cholinergic system phenotype. J. Neurosci. 2012, 32, 2002–2012. [CrossRef]
103. Kopec, B.M.; Zhao, L.; Rosa-Molinar, E.; Siahaan, T.J. Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic
Mice as a Model of Alzheimer’s Disease. Med. Res. Arch. 2020, 8. [CrossRef]
104. Braschi, C.; Capsoni, S.; Narducci, R.; Poli, A.; Sansevero, G.; Brandi, R.; Maffei, L.; Cattaneo, A.; Berardi, N. Intranasal delivery of
BDNF rescues memory deficits in AD11 mice and reduces brain microgliosis. Aging Clin. Exp. Res. 2020. [CrossRef]
105. Crews, L.; Adame, A.; Patrick, C.; Delaney, A.; Pham, E.; Rockenstein, E.; Hansen, L.; Masliah, E. Increased BMP6 levels in the
brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J. Neurosci. 2010, 30,
12252–12262. [CrossRef]
106. Burke, R.M.; Norman, T.A.; Haydar, T.F.; Slack, B.E.; Leeman, S.E.; Blusztajn, J.K.; Mellott, T.J. BMP9 ameliorates amyloidosis and
the cholinergic defect in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2013, 110, 19567–19572. [CrossRef]
107. Wang, Z.; Xiong, L.; Wan, W.; Duan, L.; Bai, X.; Zu, H. Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and
Cognitive Deficits in APP/PS1 Transgenic Mice. Front. Mol. Neurosci. 2017, 10, 32. [CrossRef]
108. Xia, L.; Zhu, X.; Zhao, Y.; Yang, G.; Zuo, X.; Xie, P.; Chen, C.; Han, Q. Genome-wide RNA sequencing analysis reveals that IGF-2
attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the
PI3K/AKT/CREB signaling pathway. Int. Psychogeriatr. 2019, 1–13. [CrossRef]
109. Mellott, T.J.; Pender, S.M.; Burke, R.M.; Langley, E.A.; Blusztajn, J.K. IGF2 ameliorates amyloidosis, increases cholinergic marker
expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer’s disease model mice.
PLoS ONE 2014, 9, e94287. [CrossRef]
110. Kiyota, T.; Ingraham, K.L.; Jacobsen, M.T.; Xiong, H.; Ikezu, T. FGF2 gene transfer restores hippocampal functions in mouse
models of Alzheimer’s disease and has therapeutic implications for neurocognitive disorders. Proc. Natl. Acad. Sci. USA 2011,
108, E1339-48. [CrossRef]
111. Chen, X.; Li, Z.; Cheng, Y.; Kardami, E.; Loh, Y.P. Low and High Molecular Weight FGF-2 Have Differential Effects on Astrocyte
Proliferation, but Are Both Protective Against Abeta-Induced Cytotoxicity. Front. Mol. Neurosci. 2019, 12, 328. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 37 of 44

112. Sun, Y.; Wang, Y.; Chen, S.T.; Chen, Y.J.; Shen, J.; Yao, W.B.; Gao, X.D.; Chen, S. Modulation of the Astrocyte-Neuron Lactate
Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21. Theranostics 2020, 10, 8430–8445. [CrossRef]
113. Patterson, S.L.; Abel, T.; Deuel, T.A.S.; Martin, K.C.; Rose, J.C.; Kandel, E.R. Recombinant BDNF Rescues Deficits in Basal Synaptic
Transmission and Hippocampal LTP in BDNF Knockout Mice. Neuron 1996, 16, 1137–1145. [CrossRef]
114. Seoane, A.; Tinsley, C.J.; Brown, M.W. Interfering with perirhinal brain-derived neurotrophic factor expression impairs recognition
memory in rats. Hippocampus 2011, 21, 121–126. [CrossRef] [PubMed]
115. Altar, C.A.; Cai, N.; Bliven, T.; Juhasz, M.; Conner, J.M.; Acheson, A.L.; Lindsay, R.M.; Wiegand, S.J. Anterograde transport of
brain-derived neurotrophic factor and its role in the brain. Nature 1997, 389, 856–860. [CrossRef] [PubMed]
116. Mizuno, M.; Yamada, K.; Olariu, A.; Nawa, H.; Nabeshima, T. Involvement of Brain-Derived Neurotrophic Factor in Spatial
Memory Formation and Maintenance in a Radial Arm Maze Test in Rats. J. Neurosci. 2000, 20, 7116–7121. [CrossRef]
117. Gorski, J.A.; Balogh, S.A.; Wehner, J.M.; Jones, K.R. Learning deficits in forebrain-restricted brain-derived neurotrophic factor
mutant mice. Neuroscience 2003, 121, 341–354. [CrossRef]
118. Carvalho, A.L.; Caldeira, M.V.; Santos, S.D.; Duarte, C.B. Role of the brain-derived neurotrophic factor at glutamatergic synapses.
Br. J. Pharmacol. 2008, 153 (Suppl. 1), S310–S324. [CrossRef]
119. Sen, A.; Nelson, T.J.; Alkon, D.L. ApoE4 and Abeta Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation. J.
Neurosci. 2015, 35, 7538–7551. [CrossRef]
120. Sen, A.; Nelson, T.J.; Alkon, D.L. ApoE isoforms differentially regulates cleavage and secretion of BDNF. Mol. Brain 2017, 10, 19.
[CrossRef]
121. Yang, J.; Harte-Hargrove, L.C.; Siao, C.J.; Marinic, T.; Clarke, R.; Ma, Q.; Jing, D.; Lafrancois, J.J.; Bath, K.G.; Mark, W.; et al.
proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep.
2014, 7, 796–806. [CrossRef]
122. Fahnestock, M.; Scott, S.A.; Jetté, N.; Weingartner, J.A.; Crutcher, K.A. Nerve growth factor mRNA and protein levels measured in
the same tissue from normal and Alzheimer’s disease parietal cortex. Mol. Brain Res. 1996, 42, 175–178. [CrossRef]
123. Jetté, N.; Cole, M.S.; Fahnestock, M. NGF mRNA is not decreased in frontal cortex from Alzheimer’s Disease patients. Mol. Brain
Res. 1994, 25, 242–250. [CrossRef]
124. Ginsberg, S.D.; Malek-Ahmadi, M.H.; Alldred, M.J.; Che, S.; Elarova, I.; Chen, Y.; Jeanneteau, F.; Kranz, T.M.; Chao, M.V.; Counts,
S.E.; et al. Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus
proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer’s disease.
Hippocampus 2019, 29, 422–439. [CrossRef]
125. Iulita, M.F.; Cuello, A.C. Nerve growth factor metabolic dysfunction in Alzheimer’s disease and Down syndrome. Trends
Pharmacol. Sci. 2014, 35, 338–348. [CrossRef]
126. Fahnestock, M.; Michalski, B.; Xu, B.; Coughlin, M.D. The Precursor Pro-Nerve Growth Factor Is the Predominant Form of Nerve
Growth Factor in Brain and Is Increased in Alzheimer’s Disease. Mol. Cell. Neurosci. 2001, 18, 210–220. [CrossRef]
127. Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Increased proNGF levels in subjects with mild cognitive impairment and mild
Alzheimer disease. J. Neuropathol. Exp. Neurol. 2004, 63, 641–649. [CrossRef] [PubMed]
128. Bruno, M.A.; Mufson, E.J.; Wuu, J.; Cuello, A.C. Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J.
Neuropathol. Exp. Neurol. 2009, 68, 1309–1318. [CrossRef]
129. Mufson, E.J.; He, B.; Nadeem, M.; Perez, S.E.; Counts, S.E.; Leurgans, S.; Fritz, J.; Lah, J.; Ginsberg, S.D.; Wuu, J.; et al. Hippocampal
ProNGF Signaling Pathways and β-Amyloid Levels in Mild Cognitive Impairment and Alzheimer Disease. J. Neuropathol. Exp.
Neurol. 2012, 71, 1018–1029. [CrossRef]
130. Fabbro, S.; Seeds, N.W. Plasminogen activator activity is inhibited while neuroserpin is up-regulated in the Alzheimer disease
brain. J. Neurochem. 2009, 109, 303–315. [CrossRef]
131. Ginsberg, S.D.; Che, S.; Wuu, J.; Counts, S.E.; Mufson, E.J. Down regulation of trk but not p75NTR gene expression in single
cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J. Neurochem. 2006, 97, 475–487. [CrossRef]
132. Podlesniy, P.; Kichev, A.; Pedraza, C.; Saurat, J.; Encinas, M.; Perez, B.; Ferrer, I.; Espinet, C. Pro-NGF from Alzheimer’s disease
and normal human brain displays distinctive abilities to induce processing and nuclear translocation of intracellular domain of
p75NTR and apoptosis. Am. J. Pathol. 2006, 169, 119–131. [CrossRef]
133. Volosin, M.; Song, W.; Almeida, R.D.; Kaplan, D.R.; Hempstead, B.L.; Friedman, W.J. Interaction of survival and death signaling
in basal forebrain neurons: Roles of neurotrophins and proneurotrophins. J. Neurosci. 2006, 26, 7756–7766. [CrossRef] [PubMed]
134. Canu, N.; Amadoro, G.; Triaca, V.; Latina, V.; Sposato, V.; Corsetti, V.; Severini, C.; Ciotti, M.T.; Calissano, P. The Intersection of
NGF/TrkA Signaling and Amyloid Precursor Protein Processing in Alzheimer’s Disease Neuropathology. Int. J. Mol. Sci. 2017,
18, 1319. [CrossRef] [PubMed]
135. Rocco, M.L.; Soligo, M.; Manni, L.; Aloe, L. Nerve Growth Factor: Early Studies and Recent Clinical Trials. Curr. Neuropharmacol.
2018, 16, 1455–1465. [CrossRef] [PubMed]
136. Poduslo, J.F.; Curran, G.L. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF,
NT-3, BDNF. Mol. Brain Res. 1996, 36, 280–286. [CrossRef]
137. Tuszynski, M.H.; Thal, L.; Pay, M.; Salmon, D.P.; Bakay, R.; Patel, P.; Blesch, A.; Vahlsing, H.L.; Ho, G.; Tong, G.; et al. A phase 1
clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005, 11, 551–555. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 38 of 44

138. Petty, B.G.; Cornblath, D.R.; Adornato, B.T.; Chaudhry, V.; Flexner, C.; Wachsman, M.; Sinicropi, D.; Burton, L.E.; Peroutka, S.J.
The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann. Neurol. 1994,
36, 244–246. [CrossRef]
139. Hefti, F.; Dravid, A.; Hartikka, J. Chronic intraventricular injections of nerve growth factor elevate hippocampal choline
acetyltransferase activity in adult rats with partial septo-hippocampal lesions. Brain Res. 1984, 293, 305–311. [CrossRef]
140. Koliatsos, V.E.; Nauta, H.J.; Clatterbuck, R.E.; Holtzman, D.M.; Mobley, W.C.; Price, D.L. Mouse nerve growth factor prevents
degeneration of axotomized basal forebrain cholinergic neurons in the monkey. J. Neurosci. 1990, 10, 3801–3813. [CrossRef]
141. Koliatsos, V.E.; Clatterbuck, R.E.; Nauta, H.J.; Knusel, B.; Burton, L.E.; Hefti, F.F.; Mobley, W.C.; Price, D.L. Human nerve growth
factor prevents degeneration of basal forebrain cholinergic neurons in primates. Ann. Neurol. 1991, 30, 831–840. [CrossRef]
142. Jönhagen, M.E.; Nordberg, A.; Amberla, K.; Bäckman, L.; Ebendal, T.; Meyerson, B.; Olson, L.; Seiger, Å.; Shigeta, M.; Theodorsson,
E.; et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement. Geriatr. Cogn.
Disord. 1998, 9, 246–257. [CrossRef]
143. Lv, Q.; Lan, W.; Sun, W.; Ye, R.; Fan, X.; Ma, M.; Yin, Q.; Jiang, Y.; Xu, G.; Dai, J.; et al. Intranasal nerve growth factor attenuates
tau phosphorylation in brain after traumatic brain injury in rats. J. Neurol. Sci. 2014, 345, 48–55. [CrossRef]
144. Tirassa, P. The nerve growth factor administrated as eye drops activates mature and precursor cells in subventricular zone of
adult rats. Arch. Ital. Biol. 2011, 149, 205–213. [CrossRef]
145. Rafii, M.S.; Baumann, T.L.; Bakay, R.A.; Ostrove, J.M.; Siffert, J.; Fleisher, A.S.; Herzog, C.D.; Barba, D.; Pay, M.; Salmon, D.P.;
et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement. 2014, 10, 571–581.
[CrossRef]
146. Eyjolfsdottir, H.; Eriksdotter, M.; Linderoth, B.; Lind, G.; Juliusson, B.; Kusk, P.; Almkvist, O.; Andreasen, N.; Blennow, K.;
Ferreira, D.; et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer’s disease patients:
Application of a second-generation encapsulated cell biodelivery device. Alzheimers Res. Ther. 2016, 8, 30. [CrossRef]
147. Lee, H.J.; Lee, J.K.; Lee, H.; Carter, J.E.; Chang, J.W.; Oh, W.; Yang, Y.S.; Suh, J.G.; Lee, B.H.; Jin, H.K.; et al. Human umbilical cord
blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse
model through modulation of neuroinflammation. Neurobiol. Aging 2012, 33, 588–602. [CrossRef]
148. Phillips, H.S.; Hains, J.M.; Armanini, M.; Laramee, G.R.; Johnson, S.A.; Winslow, J.W. BDNF mRNA is decreased in the
hippocampus of individuals with Alzheimer’s disease. Neuron 1991, 7, 695–702. [CrossRef]
149. Ferrer, I.; Marin, C.; Rey, M.J.; Ribalta, T.; Goutan, E.; Blanco, R.; Tolosa, E.; Marti, E. BDNF and full-length and truncated TrkB
expression in Alzheimer disease. Implications in therapeutic strategies. J. Neuropathol. Exp. Neurol. 1999, 58, 729–739. [CrossRef]
150. Holsinger, R.M.D.; Schnarr, J.; Henry, P.; Castelo, V.T.; Fahnestock, M. Quantitation of BDNF mRNA in human parietal cortex by
competitive reverse transcription-polymerase chain reaction: Decreased levels in Alzheimer’s disease. Mol. Brain Res. 2000, 76,
347–354. [CrossRef]
151. Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Precursor form of brain-derived neurotrophic factor and mature brain-derived
neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J. Neurochem. 2005, 93, 1412–1421. [CrossRef]
152. Buchman, A.S.; Yu, L.; Boyle, P.A.; Schneider, J.A.; De Jager, P.L.; Bennett, D.A. Higher brain BDNF gene expression is associated
with slower cognitive decline in older adults. Neurology 2016, 86, 735–741. [CrossRef]
153. Ginsberg, S.D.; Malek-Ahmadi, M.H.; Alldred, M.J.; Chen, Y.; Chen, K.; Chao, M.V.; Counts, S.E.; Mufson, E.J. Brain-derived
neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary
tangle pathology. Neurobiol. Dis. 2019, 132, 104540. [CrossRef] [PubMed]
154. Arango-Lievano, M.; Peguet, C.; Catteau, M.; Parmentier, M.-L.; Wu, S.; Chao, M.V.; Ginsberg, S.D.; Jeanneteau, F. Deletion of
Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology. Sci. Rep. 2016, 6, 37231.
[CrossRef] [PubMed]
155. Poon, W.W.; Blurton-Jones, M.; Tu, C.H.; Feinberg, L.M.; Chabrier, M.A.; Harris, J.W.; Jeon, N.L.; Cotman, C.W. beta-Amyloid
impairs axonal BDNF retrograde trafficking. Neurobiol. Aging 2011, 32, 821–833. [CrossRef] [PubMed]
156. Tanqueiro, S.R.; Ramalho, R.M.; Rodrigues, T.M.; Lopes, L.V.; Sebastiao, A.M.; Diogenes, M.J. Inhibition of NMDA Receptors
Prevents the Loss of BDNF Function Induced by Amyloid beta. Front. Pharmacol. 2018, 9, 237. [CrossRef]
157. Jeronimo-Santos, A.; Vaz, S.H.; Parreira, S.; Rapaz-Lerias, S.; Caetano, A.P.; Buee-Scherrer, V.; Castren, E.; Valente, C.A.; Blum, D.;
Sebastiao, A.M.; et al. Dysregulation of TrkB Receptors and BDNF Function by Amyloid-beta Peptide is Mediated by Calpain.
Cereb. Cortex. 2015, 25, 3107–3121. [CrossRef]
158. Bharani, K.L.; Ledreux, A.; Gilmore, A.; Carroll, S.L.; Granholm, A.-C. Serum pro-BDNF levels correlate with phospho-tau
staining in Alzheimer’s disease. Neurobiol. Aging 2020, 87, 49–59. [CrossRef]
159. Nagahara, A.H.; Merrill, D.A.; Coppola, G.; Tsukada, S.; Schroeder, B.E.; Shaked, G.M.; Wang, L.; Blesch, A.; Kim, A.; Conner,
J.M.; et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease.
Nat. Med. 2009, 15, 331–337. [CrossRef]
160. Pan, W.; Banks, W.A.; Fasold, M.B.; Bluth, J.; Kastin, A.J. Transport of brain-derived neurotrophic factor across the blood-brain
barrier. Neuropharmacology 1998, 37, 1553–1561. [CrossRef]
161. Olah, M.; Patrick, E.; Villani, A.-C.; Xu, J.; White, C.C.; Ryan, K.J.; Piehowski, P.; Kapasi, A.; Nejad, P.; Cimpean, M.; et al. A
transcriptomic atlas of aged human microglia. Nat. Commun. 2018, 9, 539. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 39 of 44

162. Felsky, D.; Roostaei, T.; Nho, K.; Risacher, S.L.; Bradshaw, E.M.; Petyuk, V.; Schneider, J.A.; Saykin, A.; Bennett, D.A.; De Jager, P.L.
Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat. Commun. 2019, 10,
409. [CrossRef] [PubMed]
163. Jann, J.; Gascon, S.; Roux, S.; Faucheux, N. Influence of the TGF-beta Superfamily on Osteoclasts/Osteoblasts Balance in
Physiological and Pathological Bone Conditions. Int. J. Mol. Sci. 2020, 21, 7537. [CrossRef] [PubMed]
164. Kingsley, D.M. The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms.
Genes Dev. 1994, 8, 133–146. [CrossRef] [PubMed]
165. Brown, M.A.; Zhao, Q.; Baker, K.A.; Naik, C.; Chen, C.; Pukac, L.; Singh, M.; Tsareva, T.; Parice, Y.; Mahoney, A.; et al. Crystal
structure of BMP-9 and functional interactions with pro-region and receptors. J. Biol. Chem. 2005, 280, 25111–25118. [CrossRef]
166. Cao, X.; Chen, D. The BMP signaling and in vivo bone formation. Gene 2005, 357, 1–8. [CrossRef]
167. Luo, G.; Hofmann, C.; Bronckers, A.L.; Sohocki, M.; Bradley, A.; Karsenty, G. BMP-7 is an inducer of nephrogenesis, and is also
required for eye development and skeletal patterning. Genes Dev. 1995, 9, 2808–2820. [CrossRef]
168. Zhao, G.Q. Consequences of knocking out BMP signaling in the mouse. Genesis 2003, 35, 43–56. [CrossRef]
169. Bakrania, P.; Efthymiou, M.; Klein, J.C.; Salt, A.; Bunyan, D.J.; Wyatt, A.; Ponting, C.P.; Martin, A.; Williams, S.; Lindley, V.; et al.
Mutations in BMP4 cause eye, brain, and digit developmental anomalies: Overlap between the BMP4 and hedgehog signaling
pathways. Am. J. Hum. Genet. 2008, 82, 304–319. [CrossRef]
170. Bidart, M.; Ricard, N.; Levet, S.; Samson, M.; Mallet, C.; David, L.; Subileau, M.; Tillet, E.; Feige, J.J.; Bailly, S. BMP9 is produced
by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell Mol. Life Sci. 2012, 69, 313–324.
[CrossRef]
171. Wohl, A.P.; Troilo, H.; Collins, R.F.; Baldock, C.; Sengle, G. Extracellular Regulation of Bone Morphogenetic Protein Activity by
the Microfibril Component Fibrillin-1. J. Biol. Chem. 2016, 291, 12732–12746. [CrossRef]
172. Heldin, C.-H.; Miyazono, K.; ten Dijke, P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 1997,
390, 465–471. [CrossRef]
173. Scharpfenecker, M.; van Dinther, M.; Liu, Z.; van Bezooijen, R.L.; Zhao, Q.; Pukac, L.; Lowik, C.W.; ten Dijke, P. BMP-9 signals via
ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J. Cell Sci. 2007, 120, 964–972.
[CrossRef]
174. Yadin, D.; Knaus, P.; Mueller, T.D. Structural insights into BMP receptors: Specificity, activation and inhibition. Cytokine Growth.
Factor Rev. 2016, 27, 13–34. [CrossRef]
175. Okadome, T.; Yamashita, H.; Franzén, P.; Morén, A.; Heldin, C.H.; Miyazono, K. Distinct roles of the intracellular domains
of transforming growth factor-beta type I and type II receptors in signal transduction. J. Biol. Chem. 1994, 269, 30753–30756.
[CrossRef]
176. Hinck, A.P. Structural studies of the TGF-betas and their receptors—Insights into evolution of the TGF-beta superfamily. FEBS
Lett. 2012, 586, 1860–1870. [CrossRef]
177. Mi, L.Z.; Brown, C.T.; Gao, Y.; Tian, Y.; Le, V.Q.; Walz, T.; Springer, T.A. Structure of bone morphogenetic protein 9 procomplex.
Proc. Natl. Acad. Sci. USA 2015, 112, 3710–3715. [CrossRef]
178. Salmon, R.M.; Guo, J.; Wood, J.H.; Tong, Z.; Beech, J.S.; Lawera, A.; Yu, M.; Grainger, D.J.; Reckless, J.; Morrell, N.W.; et al.
Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Nat. Commun. 2020, 11, 1621.
[CrossRef]
179. Charytoniuk, D.A.; Traiffort, E.; Pinard, E.; Issertial, O.; Seylaz, J.; Ruat, M. Distribution of bone morphogenetic protein and
bone morphogenetic protein receptor transcripts in the rodent nervous system and up-regulation of bone morphogenetic protein
receptor type II in hippocampal dentate gyrus in a rat model of global cerebral ischemia. Neuroscience 2000, 100, 33–43. [CrossRef]
[PubMed]
180. Mira, H.; Andreu, Z.; Suh, H.; Lie, D.C.; Jessberger, S.; Consiglio, A.; San Emeterio, J.; Hortiguela, R.; Marques-Torrejon, M.A.;
Nakashima, K.; et al. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult
hippocampus. Cell Stem. Cell 2010, 7, 78–89. [CrossRef]
181. Gipson, G.R.; Goebel, E.J.; Hart, K.N.; Kappes, E.C.; Kattamuri, C.; McCoy, J.C.; Thompson, T.B. Structural perspective of BMP
ligands and signaling. Bone 2020, 140, 115549. [CrossRef]
182. Nohe, A.; Hassel, S.; Ehrlich, M.; Neubauer, F.; Sebald, W.; Henis, Y.I.; Knaus, P. The mode of bone morphogenetic protein (BMP)
receptor oligomerization determines different BMP-2 signaling pathways. J. Biol. Chem. 2002, 277, 5330–5338. [CrossRef]
183. Ehrlich, M. Endocytosis and trafficking of BMP receptors: Regulatory mechanisms for fine-tuning the signaling response in
different cellular contexts. Cytokine Growth. Factor Rev. 2016, 27, 35–42. [CrossRef]
184. Higashi, T.; Tanaka, S.; Iida, T.; Okabe, S. Synapse Elimination Triggered by BMP4 Exocytosis and Presynaptic BMP Receptor
Activation. Cell Rep. 2018, 22, 919–929. [CrossRef]
185. Lauzon, M.A.; Daviau, A.; Marcos, B.; Faucheux, N. Growth factor treatment to overcome Alzheimer’s dysfunctional signaling.
Cell Signal. 2015, 27, 1025–1038. [CrossRef] [PubMed]
186. Onichtchouk, D.; Chen, Y.G.; Dosch, R.; Gawantka, V.; Delius, H.; Massague, J.; Niehrs, C. Silencing of TGF-beta signalling by the
pseudoreceptor BAMBI. Nature 1999, 401, 480–485. [CrossRef] [PubMed]
187. Miyazawa, K.; Miyazono, K. Regulation of TGF-beta Family Signaling by Inhibitory Smads. Cold Spring Harb. Perspect. Biol. 2017,
9. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 6071 40 of 44

188. Lopez-Coviella, I.; Follettie, M.T.; Mellott, T.J.; Kovacheva, V.P.; Slack, B.E.; Diesl, V.; Berse, B.; Thies, R.S.; Blusztajn, J.K. Bone
morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proc. Natl. Acad. Sci. USA 2005, 102,
6984–6989. [CrossRef] [PubMed]
189. Schnitzler, A.C.; Lopez-Coviella, I.; Blusztajn, J.K. Differential modulation of nerve growth factor receptor (p75) and cholinergic
gene expression in purified p75-expressing and non-expressing basal forebrain neurons by BMP9. Brain Res. 2008, 1246, 19–28.
[CrossRef]
190. Schnitzler, A.C.; Mellott, T.J.; Lopez-Coviella, I.; Tallini, Y.N.; Kotlikoff, M.I.; Follettie, M.T.; Blusztajn, J.K. BMP9 (bone morpho-
genetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons. J.
Neurosci. 2010, 30, 8221–8228. [CrossRef]
191. Dinh Duong, T.A.; Hoshiba, Y.; Saito, K.; Kawasaki, K.; Ichikawa, Y.; Matsumoto, N.; Shinmyo, Y.; Kawasaki, H. FGF Signaling
Directs the Cell Fate Switch from Neurons to Astrocytes in the Developing Mouse Cerebral Cortex. J. Neurosci. 2019, 39, 6081–6094.
[CrossRef]
192. Guillemot, F.; Zimmer, C. From cradle to grave: The multiple roles of fibroblast growth factors in neural development. Neuron
2011, 71, 574–588. [CrossRef]
193. Mikawa, S.; Wang, C.; Sato, K. Bone morphogenetic protein-4 expression in the adult rat brain. J. Comp. Neurol. 2006, 499, 613–625.
[CrossRef]
194. Wagner, D.O.; Sieber, C.; Bhushan, R.; Borgermann, J.H.; Graf, D.; Knaus, P. BMPs: From bone to body morphogenetic proteins.
Sci. Signal. 2010, 3, mr1. [CrossRef]
195. Sato, T.; Mikawa, S.; Sato, K. BMP2 expression in the adult rat brain. J. Comp. Neurol. 2010, 518, 4513–4530. [CrossRef]
196. Kusakawa, Y.; Mikawa, S.; Sato, K. BMP5 expression in the adult rat brain. Neuroscience 2015, 284, 972–987. [CrossRef]
197. Hayashi, Y.; Mikawa, S.; Ogawa, C.; Masumoto, K.; Katou, F.; Sato, K. BMP6 expression in the adult rat central nervous system. J.
Chem. Neuroanat. 2019, 98, 41–54. [CrossRef]
198. López-Coviella, I.; Berse, B.; Krauss, R.; Thies, R.S.; Blusztajn, J.K. Induction and Maintenance of the Neuronal Cholinergic
Phenotype in the Central Nervous System by BMP-9. Science 2000, 289, 313–316. [CrossRef]
199. Chen, H.L.; Lein, P.J.; Wang, J.Y.; Gash, D.; Hoffer, B.J.; Chiang, Y.H. Expression of bone morphogenetic proteins in the brain
during normal aging and in 6-hydroxydopamine-lesioned animals. Brain Res. 2003, 994, 81–90. [CrossRef]
200. Hart, C.G.; Karimi-Abdolrezaee, S. Bone morphogenetic proteins: New insights into their roles and mechanisms in CNS
development, pathology and repair. Exp. Neurol. 2020, 334, 113455. [CrossRef]
201. Bond, A.M.; Bhalala, O.G.; Kessler, J.A. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation.
Dev. Neurobiol. 2012, 72, 1068–1084. [CrossRef]
202. Feng, Y.; Hu, Y. Bone morphogenetic protein 9 serves a protective role in response to ischemicreperfusion in the brain by
promoting ERK activation. Mol. Med. Rep. 2018, 17, 2845–2852. [CrossRef]
203. Lopez-Coviella, I.; Mellott, T.J.; Schnitzler, A.C.; Blusztajn, J.K. BMP9 protects septal neurons from axotomy-evoked loss of
cholinergic phenotype. PLoS ONE 2011, 6, e21166. [CrossRef] [PubMed]
204. Yousef, H.; Morgenthaler, A.; Schlesinger, C.; Bugaj, L.; Conboy, I.M.; Schaffer, D.V. Age-Associated Increase in BMP Signaling
Inhibits Hippocampal Neurogenesis. Stem Cells. 2015, 33, 1577–1588. [CrossRef] [PubMed]
205. Li, D.; Tang, J.; Xu, H.; Fan, X.; Bai, Y.; Yang, L. Decreased hippocampal cell proliferation correlates with increased expression of
BMP4 in the APPswe/PS1DeltaE9 mouse model of Alzheimer’s disease. Hippocampus 2008, 18, 692–698. [CrossRef] [PubMed]
206. Adams, S.L.; Benayoun, L.; Tilton, K.; Mellott, T.J.; Seshadri, S.; Blusztajn, J.K.; Delalle, I. Immunohistochemical Analysis of
Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During
Progression of Alzheimer’s Disease. J. Alzheimers Dis. 2018, 63, 1433–1443. [CrossRef] [PubMed]
207. Klimaschewski, L.; Claus, P. Fibroblast Growth Factor Signalling in the Diseased Nervous System. Mol. Neurobiol. 2021. [CrossRef]
208. Ornitz, D.M.; Itoh, N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 2015, 4, 215–266.
[CrossRef]
209. Arnaud, E.; Touriol, C.; Boutonnet, C.; Gensac, M.C.; Vagner, S.; Prats, H.; Prats, A.C. A new 34-kilodalton isoform of human
fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor. Mol.
Cell Biol. 1999, 19, 505–514. [CrossRef]
210. Touriol, C.; Bornes, S.; Bonnal, S.; Audigier, S.; Prats, H.; Prats, A.-C.; Vagner, S. Generation of protein isoform diversity by
alternative initiation of translation at non-AUG codons. Biol. Cell 2003, 95, 169–178. [CrossRef]
211. Beenken, A.; Mohammadi, M. The FGF family: Biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 2009, 8, 235–253.
[CrossRef]
212. Turner, C.A.; Eren-Kocak, E.; Inui, E.G.; Watson, S.J.; Akil, H. Dysregulated fibroblast growth factor (FGF) signaling in neurological
and psychiatric disorders. Semin. Cell Dev. Biol. 2016, 53, 136–143. [CrossRef]
213. Asai, T.; Wanaka, A.; Kato, H.; Masana, Y.; Seo, M.; Tohyama, M. Differential expression of two members of FGF receptor gene
family, FGFR-1 and FGFR-2 mRNA, in the adult rat central nervous system. Mol. Brain Res. 1993, 17, 174–178. [CrossRef]
214. Miyake, A.; Hattori, Y.; Ohta, M.; Itoh, N. Rat oligodendrocytes and astrocytes preferentially express fibroblast growth factor
receptor-2 and -3 mRNAs. J. Neurosci. Res. 1996, 45, 534–541. [CrossRef]
215. Latko, M.; Czyrek, A.; Porebska, N.; Kucinska, M.; Otlewski, J.; Zakrzewska, M.; Opalinski, L. Cross-Talk between Fibroblast
Growth Factor Receptors and Other Cell Surface Proteins. Cells 2019, 8, 455. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 41 of 44

216. Matsumoto, N.; Shinmyo, Y.; Ichikawa, Y.; Kawasaki, H. Gyrification of the cerebral cortex requires FGF signaling in the
mammalian brain. Elife 2017, 6. [CrossRef]
217. Werner, S.; Unsicker, K.; von Bohlen und Halbach, O. Fibroblast growth factor-2 deficiency causes defects in adult hippocampal
neurogenesis, which are not rescued by exogenous fibroblast growth factor-2. J. Neurosci. Res. 2011, 89, 1605–1617. [CrossRef]
218. Gonzalez, A.M.; Berry, M.; Maher, P.A.; Logan, A.; Baird, A. A comprehensive analysis of the distribution of FGF-2 and FGFR1 in
the rat brain. Brain Res. 1995, 701, 201–226. [CrossRef]
219. Katsouri, L.; Ashraf, A.; Birch, A.M.; Lee, K.K.; Mirzaei, N.; Sastre, M. Systemic administration of fibroblast growth factor-2
(FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice. Neurobiol. Aging 2015, 36, 821–831. [CrossRef]
220. Feng, C.; Zhang, C.; Shao, X.; Liu, Q.; Qian, Y.; Feng, L.; Chen, J.; Zha, Y.; Zhang, Q.; Jiang, X. Enhancement of nose-to-brain
delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and
ibotenic acid into the bilateral hippocampus. Int. J. Pharm. 2012, 423, 226–234. [CrossRef]
221. Pasquin, S.; Sharma, M.; Gauchat, J.F. Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegen-
erative and metabolic syndrome pathologies. Cytokine Growth. Factor Rev. 2015, 26, 507–515. [CrossRef]
222. Rollero, A.; Murialdo, G.; Fonzi, S.; Garrone, S.; Gianelli, M.V.; Gazzerro, E.; Barreca, A.; Polleri, A. Relationship between cognitive
function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology 1998, 38, 73–79.
[CrossRef]
223. Aleman, A.; Verhaar, H.J.; De Haan, E.H.; De Vries, W.R.; Samson, M.M.; Drent, M.L.; Van der Veen, E.A.; Koppeschaar, H.P.
Insulin-like growth factor-I and cognitive function in healthy older men. J. Clin. Endocrinol. Metab. 1999, 84, 471–475. [CrossRef]
224. Tumati, S.; Burger, H.; Martens, S.; van der Schouw, Y.T.; Aleman, A. Association between Cognition and Serum Insulin-Like
Growth Factor-1 in Middle-Aged & Older Men: An 8 Year Follow-Up Study. PLoS ONE 2016, 11, e0154450. [CrossRef]
225. Carro, E.; Trejo, J.L.; Gomez-Isla, T.; LeRoith, D.; Torres-Aleman, I. Serum insulin-like growth factor I regulates brain amyloid-beta
levels. Nat. Med. 2002, 8, 1390–1397. [CrossRef]
226. Carro, E.; Trejo, J.L.; Gerber, A.; Loetscher, H.; Torrado, J.; Metzger, F.; Torres-Aleman, I. Therapeutic actions of insulin-like growth
factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol. Aging 2006, 27, 1250–1257. [CrossRef]
227. Lanz, T.A.; Salatto, C.T.; Semproni, A.R.; Marconi, M.; Brown, T.M.; Richter, K.E.G.; Schmidt, K.; Nelson, F.R.; Schachter, J.B.
Peripheral elevation of IGF-1 fails to alter Aβ clearance in multiple in vivo models. Biochem. Pharmacol. 2008, 75, 1093–1103.
[CrossRef]
228. Sohrabi, M.; Floden, A.M.; Manocha, G.D.; Klug, M.G.; Combs, C.K. IGF-1R Inhibitor Ameliorates Neuroinflammation in an
Alzheimer’s Disease Transgenic Mouse Model. Front. Cell Neurosci. 2020, 14, 200. [CrossRef]
229. Sevigny, J.J.; Ryan, J.M.; van Dyck, C.H.; Peng, Y.; Lines, C.R.; Nessly, M.L. Growth hormone secretagogue MK-677: No clinical
effect on AD progression in a randomized trial. Neurology 2008, 71, 1702–1708. [CrossRef] [PubMed]
230. Antipova, T.A.; Gudasheva, T.A.; Seredenin, S.B. In Vitro Study of Neuroprotective Properties of GK-2, a New Original Nerve
Growth Factor Mimetic. Bull. Exp. Biol. Med. 2011, 150, 607–609. [CrossRef] [PubMed]
231. Gudasheva, T.A.; Antipova, T.A.; Seredenin, S.B. Novel low-molecular-weight mimetics of the nerve growth factor. Dokl. Biochem.
Biophys. 2010, 434, 262–265. [CrossRef] [PubMed]
232. Naletova, I.; Satriano, C.; Pietropaolo, A.; Giani, F.; Pandini, G.; Triaca, V.; Amadoro, G.; Latina, V.; Calissano, P.; Travaglia, A.;
et al. The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides.
Cells 2019, 8, 301. [CrossRef] [PubMed]
233. Yaar, M.; Zhai, S.; Panova, I.; Fine, R.E.; Eisenhauer, P.B.; Blusztajn, J.K.; Lopez-Coviella, I.; Gilchrest, B.A. A cyclic peptide that
binds p75(NTR) protects neurones from beta amyloid (1-40)-induced cell death. Neuropathol. Appl. Neurobiol. 2007, 33, 533–543.
[CrossRef]
234. Povarnina, P.Y.; Vorontsova, O.N.; Gudasheva, T.A.; Ostrovskaya, R.U.; Seredenin, S.B. Original Nerve Growth Factor Mimetic
Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease. Acta Nat. 2013, 5, 84–91. [CrossRef]
235. Gudasheva, T.A.; Povarnina, P.Y.; Volkova, A.A.; Kruglov, S.V.; Antipova, T.A.; Seredenin, S.B. A Nerve Growth Factor Dipeptide
Mimetic Stimulates Neurogenesis and Synaptogenesis in the Hippocampus and Striatum of Adult Rats with Focal Cerebral
Ischemia. Acta Nat. 2019, 11, 31–37. [CrossRef] [PubMed]
236. Colangelo, A.M.; Bianco, M.R.; Vitagliano, L.; Cavaliere, C.; Cirillo, G.; De Gioia, L.; Diana, D.; Colombo, D.; Redaelli, C.;
Zaccaro, L.; et al. A new nerve growth factor-mimetic peptide active on neuropathic pain in rats. J. Neurosci. 2008, 28, 2698–2709.
[CrossRef]
237. Cardenas-Aguayo, M.d.C.; Kazim, S.F.; Grundke-Iqbal, I.; Iqbal, K. Neurogenic and neurotrophic effects of BDNF peptides in
mouse hippocampal primary neuronal cell cultures. PLoS ONE 2013, 8, e53596. [CrossRef]
238. Gudasheva, T.A.; Tallerova, A.V.; Mezhlumyan, A.G.; Antipova, T.A.; Logvinov, I.O.; Firsova, Y.N.; Povarnina, P.Y.; Seredenin, S.B.
Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social
Defeat Stress. Biomolecules 2021, 11, 252. [CrossRef]
239. Lauzon, M.A.; Drevelle, O.; Faucheux, N. Peptides derived from the knuckle epitope of BMP-9 induce the cholinergic differentia-
tion and inactivate GSk3beta in human SH-SY5Y neuroblastoma cells. Sci. Rep. 2017, 7, 4695. [CrossRef]
240. Lauzon, M.A.; Faucheux, N. A small peptide derived from BMP-9 can increase the effect of bFGF and NGF on SH-SY5Y cells
differentiation. Mol. Cell Neurosci. 2018, 88, 83–92. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 42 of 44

241. Rampazzo, E.; Dettin, M.; Maule, F.; Scabello, A.; Calvanese, L.; D’Auria, G.; Falcigno, L.; Porcu, E.; Zamuner, A.; Della Puppa, A.;
et al. A synthetic BMP-2 mimicking peptide induces glioblastoma stem cell differentiation. Biochim. Biophys. Acta Gen. Subj. 2017,
1861, 2282–2292. [CrossRef]
242. Xiong, S.; Ma, M.; Xu, Y.; Wei, F.; Gu, Q.; He, X.; Xu, X. Protective effects of peptide FK18 against neuro-excitotoxicity in SH-SY5Y
cells. Exp. Ther. Med. 2021, 21, 451. [CrossRef]
243. Gudasheva, T.A.; Povarnina, P.Y.; Antipova, T.A.; Firsova, Y.N.; Konstantinopolsky, M.A.; Seredenin, S.B. Dimeric dipeptide
mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction.
J. Biomed. Sci. 2015, 22, 106. [CrossRef] [PubMed]
244. Fletcher, J.M.; Morton, C.J.; Zwar, R.A.; Murray, S.S.; O’Leary, P.D.; Hughes, R.A. Design of a conformationally defined and
proteolytically stable circular mimetic of brain-derived neurotrophic factor. J. Biol. Chem. 2008, 283, 33375–33383. [CrossRef]
245. Gudasheva, T.A.; Logvinov, I.O.; Antipova, T.A.; Seredenin, S.B. Brain-derived neurotrophic factor loop 4 dipeptide mimetic
GSB-106 activates TrkB, Erk, and Akt and promotes neuronal survival in vitro. Dokl. Biochem. Biophys. 2013, 451, 212–214.
[CrossRef] [PubMed]
246. Longo, F.M.; Vu, T.K.; Mobley, W.C. The in vitro biological effect of nerve growth factor is inhibited by synthetic peptides. Cell
Regul. 1990, 1, 189–195. [CrossRef]
247. Ibáñez, C.F.; Ebendal, T.; Barbany, G.; Murray-Rust, J.; Blundell, T.L.; Persson, H. Disruption of the low affinity receptor-binding
site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell 1992, 69, 329–341. [CrossRef]
248. McDonald, N.Q.; Lapatto, R.; Murray-Rust, J.; Blundell, T.L. X-ray crystallographic studies on murine nerve growth factor. J. Cell
Sci. Suppl. 1990, 13, 19–30. [CrossRef]
249. LeSauteur, L.; Wei, L.; Gibbs, B.F.; Saragovi, H.U. Small peptide mimics of nerve growth factor bind TrkA receptors and affect
biological responses. J. Biol. Chem. 1995, 270, 6564–6569. [CrossRef]
250. Maliartchouk, S.; Debeir, T.; Beglova, N.; Cuello, A.C.; Gehring, K.; Saragovi, H.U. Genuine monovalent ligands of TrkA nerve
growth factor receptors reveal a novel pharmacological mechanism of action. J. Biol. Chem. 2000, 275, 9946–9956. [CrossRef]
251. Longo, F.M.; Manthorpe, M.; Xie, Y.M.; Varon, S. Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-
dependent mechanism. J. Neurosci. Res. 1997, 48, 1–17. [CrossRef]
252. Gudasheva, T.A.; Tarasiuk, A.V.; Sazonova, N.M.; Pomogaibo, S.V.; Shumskiy, A.N.; Logvinov, I.O.; Nikolaev, S.V.; Povarnina,
P.Y.; Konstantinopolsky, M.A.; Antipova, T.A.; et al. Design, synthesis, and neuroprotective effects of a dimeric dipeptide mimetic
of the third loop of the nerve growth factor. Russ. J. Bioorganic Chem. 2017, 43, 235–247. [CrossRef]
253. Woo, S.B.; Neet, K.E. Characterization of histidine residues essential for receptor binding and activity of nerve growth factor. J.
Biol. Chem. 1996, 271, 24433–24441. [CrossRef]
254. Shih, A.; Laramee, G.R.; Schmelzer, C.H.; Burton, L.E.; Winslow, J.W. Mutagenesis identifies amino-terminal residues of nerve
growth factor necessary for Trk receptor binding and biological activity. J. Biol. Chem. 1994, 269, 27679–27686. [CrossRef]
255. Berrera, M.; Cattaneo, A.; Carloni, P. Molecular simulation of the binding of nerve growth factor peptide mimics to the receptor
tyrosine kinase A. Biophys. J. 2006, 91, 2063–2071. [CrossRef]
256. Travaglia, A.; Arena, G.; Fattorusso, R.; Isernia, C.; La Mendola, D.; Malgieri, G.; Nicoletti, V.G.; Rizzarelli, E. The inorganic
perspective of nerve growth factor: Interactions of Cu2+ and Zn2+ with the N-terminus fragment of nerve growth factor
encompassing the recognition domain of the TrkA receptor. Chemistry 2011, 17, 3726–3738. [CrossRef] [PubMed]
257. Travaglia, A.; Pietropaolo, A.; Di Martino, R.; Nicoletti, V.G.; La Mendola, D.; Calissano, P.; Rizzarelli, E. A small linear peptide
encompassing the NGF N-terminus partly mimics the biological activities of the entire neurotrophin in PC12 cells. ACS Chem.
Neurosci. 2015, 6, 1379–1392. [CrossRef] [PubMed]
258. Pandini, G.; Satriano, C.; Pietropaolo, A.; Giani, F.; Travaglia, A.; La Mendola, D.; Nicoletti, V.G.; Rizzarelli, E. The Inorganic Side
of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition
Domain of TrkA Receptor. Front. Neurosci. 2016, 10, 569. [CrossRef]
259. Liu, Y.; Nguyen, M.; Robert, A.; Meunier, B. Metal Ions in Alzheimer’s Disease: A Key Role or Not? Acc. Chem. Res. 2019, 52,
2026–2035. [CrossRef]
260. Stelmashook, E.V.; Genrikhs, E.E.; Novikova, S.V.; Barskov, I.V.; Gudasheva, T.A.; Seredenin, S.B.; Khaspekov, L.G.; Isaev, N.K.
Behavioral effect of dipeptide NGF mimetic GK-2 in an in vivo model of rat traumatic brain injury and its neuroprotective and
regenerative properties in vitro. Int. J. Neurosci. 2015, 125, 375–379. [CrossRef]
261. Povarnina, P.Y.; Gudasheva, T.A.; Vorontsova, O.N.; Bondarenko, N.A.; Seredenin, S.B. Antiparkinsonian Properties of a Nerve
Growth Factor Dipeptide Mimetic GK-2 in in Vivo Experiments. Bull. Exp. Biol. Med. 2011, 151, 690. [CrossRef]
262. Soumen, R.; Johnston, A.H.; Moin, S.T.; Dudas, J.; Newman, T.A.; Hausott, B.; Schrott-Fischer, A.; Glueckert, R. Activation of TrkB
receptors by NGFbeta mimetic peptide conjugated polymersome nanoparticles. Nanomedicine 2012, 8, 271–274. [CrossRef]
263. O’Leary, P.D.; Hughes, R.A. Structure-activity relationships of conformationally constrained peptide analogues of loop 2 of
brain-derived neurotrophic factor. J. Neurochem. 1998, 70, 1712–1721. [CrossRef] [PubMed]
264. Ibáñez, C.F.; Ebendal, T.; Persson, H. Chimeric molecules with multiple neurotrophic activities reveal structural elements
determining the specificities of NGF and BDNF. EMBO J. 1991, 10, 2105–2110. [CrossRef]
265. Ibáñez, C.F.; Ilag, L.L.; Murray-Rust, J.; Persson, H. An extended surface of binding to Trk tyrosine kinase receptors in NGF and
BDNF allows the engineering of a multifunctional pan-neurotrophin. EMBO J. 1993, 12, 2281–2293. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 43 of 44

266. O’Leary, P.D.; Hughes, R.A. Design of potent peptide mimetics of brain-derived neurotrophic factor. J. Biol. Chem. 2003, 278,
25738–25744. [CrossRef] [PubMed]
267. Fletcher, J.M.; Hughes, R.A. Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency,
proteolytic stability and transmembrane passage in vitro. Bioorg. Med. Chem. 2009, 17, 2695–2702. [CrossRef] [PubMed]
268. Zainullina, L.F.; Vakhitova, Y.V.; Lusta, A.Y.; Gudasheva, T.A.; Seredenin, S.B. Dimeric mimetic of BDNF loop 4 promotes survival
of serum-deprived cell through TrkB-dependent apoptosis suppression. Sci. Rep. 2021, 11, 7781. [CrossRef] [PubMed]
269. Fobian, K.; Owczarek, S.; Budtz, C.; Bock, E.; Berezin, V.; Pedersen, M.V. Peptides derived from the solvent-exposed loops 3 and 4
of BDNF bind TrkB and p75(NTR) receptors and stimulate neurite outgrowth and survival. J. Neurosci. Res. 2010, 88, 1170–1181.
[CrossRef] [PubMed]
270. Seredenin, S.B.; Voronina, T.A.; Gudasheva, T.A.; Garibova, T.L.; Molodavkin, G.M.; Litvinova, S.A.; Elizarova, E.A.; Poseva, V.I.
Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF. Acta Nat. 2013, 5,
105–109. [CrossRef]
271. Gudasheva, T.A.; Povarnina, P.; Logvinov, I.O.; Antipova, T.A.; Seredenin, S.B. Mimetics of brain-derived neurotrophic factor
loops 1 and 4 are active in a model of ischemic stroke in rats. Drug Des. Devel. Ther. 2016, 10, 3545–3553. [CrossRef]
272. Kolyvanov, G.B.; Zherdev, V.P.; Gribakina, O.G.; Bochkov, P.O.; Shevchenko, R.V.; Litvin, A.A.; Blynskaya, E.V.; Bueva, V.V.
Comparative Preclinical Pharmacokinetics and Bioavailability of Antidepressant GSB-106 Tablet Form. Bull. Exp. Biol. Med. 2019,
167, 637–640. [CrossRef]
273. Povarnina, P.Y.; Garibova, T.L.; Gudasheva, T.A.; Seredenin, S.B. Antidepressant Effect of an Orally Administered Dipeptide
Mimetic of the Brain-Derived Neurotrophic Factor. Acta Nat. 2018, 10, 81–84. [CrossRef]
274. Saito, A.; Suzuki, Y.; Ogata, S.; Ohtsuki, C.; Tanihara, M. Accelerated bone repair with the use of a synthetic BMP-2-derived
peptide and bone-marrow stromal cells. J. Biomed. Mater. Res. A 2005, 72, 77–82. [CrossRef]
275. Bergeron, E.; Marquis, M.E.; Chretien, I.; Faucheux, N. Differentiation of preosteoblasts using a delivery system with BMPs and
bioactive glass microspheres. J. Mater. Sci. Mater. Med. 2007, 18, 255–263. [CrossRef]
276. Beauvais, S.; Drevelle, O.; Lauzon, M.A.; Daviau, A.; Faucheux, N. Modulation of MAPK signalling by immobilized adhesive
peptides: Effect on stem cell response to BMP-9-derived peptides. Acta Biomater. 2016, 31, 241–251. [CrossRef]
277. Lauzon, M.A.; Marcos, B.; Faucheux, N. Characterization of alginate/chitosan-based nanoparticles and mathematical modeling
of their SpBMP-9 release inducing neuronal differentiation of human SH-SY5Y cells. Carbohydr. Polym. 2018, 181, 801–811.
[CrossRef]
278. Arranz, A.M.; De Strooper, B. The role of astroglia in Alzheimer’s disease: Pathophysiology and clinical implications. Lancet
Neurol. 2019, 18, 406–414. [CrossRef]
279. Baird, A.; Schubert, D.; Ling, N.; Guillemin, R. Receptor- and heparin-binding domains of basic fibroblast growth factor. Proc.
Natl. Acad. Sci. USA 1988, 85, 2324–2328. [CrossRef]
280. Xiong, S.; Xu, Y.; Ma, M.; Wang, H.; Wei, F.; Gu, Q.; Xu, X. Neuroprotective effects of a novel peptide, FK18, under oxygen-glucose
deprivation in SH-SY5Y cells and retinal ischemia in rats via the Akt pathway. Neurochem. Int. 2017, 108, 78–90. [CrossRef]
281. Plotnikov, A.N.; Schlessinger, J.; Hubbard, S.R.; Mohammadi, M. Structural Basis for FGF Receptor Dimerization and Activation.
Cell 1999, 98, 641–650. [CrossRef]
282. Manfe, V.; Kochoyan, A.; Bock, E.; Berezin, V. Peptides derived from specific interaction sites of the fibroblast growth factor 2-FGF
receptor complexes induce receptor activation and signaling. J. Neurochem. 2010, 114, 74–86. [CrossRef]
283. Guan, J.; Waldvogel, H.J.; Faull, R.L.M.; Gluckman, P.D.; Williams, C.E. The effects of the N-terminal tripeptide of insulin-like
growth factor-1, glycine-proline-glutamate in different regions following hypoxic-ischemic brain injury in adult rats. Neuroscience
1999, 89, 649–659. [CrossRef]
284. Baker, A.M.; Batchelor, D.C.; Thomas, G.B.; Wen, J.Y.; Rafiee, M.; Lin, H.; Guan, J. Central penetration and stability of N-terminal
tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat. Neuropeptides 2005, 39, 81–87. [CrossRef]
[PubMed]
285. Sara, V.R.; Carlsson-Skwirut, C.; Bergman, T.; Jörnvall, H.; Roberts, P.J.; Crawford, M.; Håkansson, L.N.; Civalero, I.; Nordberg, A.
Identification of Gly-Pro-Glu (GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncated in brain, as a
novel neuroactive peptide. Biochem. Biophys. Res. Commun. 1989, 165, 766–771. [CrossRef]
286. Nilsson-Håkansson, L.; Civalero, I.; Zhang, X.; Carlsson-Skwirut, C.; Sara, V.R.; Nordberg, A. Effects of IGF-1, truncated IGF-1
and the tripeptide Gly-Pro-Glu on acetylcholine release from parietal cortex of rat brain. Neuroreport 1993, 4, 1111–1114.
287. Saura, J.; Curatolo, L.; Williams, C.E.; Gatti, S.; Benatti, L.; Peeters, C.; Guan, J.; Dragunow, M.; Post, C.; Faull, R.L.; et al.
Neuroprotective effects of Gly-Pro-Glu, the N- terminal tripeptide of IGF-1, in the hippocampus in vitro. NeuroReport 1999, 10,
161–164. [CrossRef]
288. Marinelli, L.; Fornasari, E.; Di Stefano, A.; Turkez, H.; Arslan, M.E.; Eusepi, P.; Ciulla, M.; Cacciatore, I. (R)-alpha-Lipoyl-
Gly-l-Pro-l-Glu dimethyl ester as dual acting agent for the treatment of Alzheimer’s disease. Neuropeptides 2017, 66, 52–58.
[CrossRef]
289. Marinelli, L.; Fornasari, E.; Di Stefano, A.; Turkez, H.; Genovese, S.; Epifano, F.; Di Biase, G.; Costantini, E.; D’Angelo, C.; Reale,
M.; et al. Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents. Bioorg. Med.
Chem. Lett. 2019, 29, 194–198. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 6071 44 of 44

290. Blanchard, J.; Chohan, M.O.; Li, B.; Liu, F.; Iqbal, K.; Grundke-Iqbal, I. Beneficial effect of a CNTF tetrapeptide on adult
hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice. J. Alzheimers Dis. 2010, 21, 1185–1195. [CrossRef]
291. Chohan, M.O.; Li, B.; Blanchard, J.; Tung, Y.C.; Heaney, A.T.; Rabe, A.; Iqbal, K.; Grundke-Iqbal, I. Enhancement of dentate gyrus
neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol. Aging 2011, 32, 1420–1434.
[CrossRef]
292. Blanchard, J.; Wanka, L.; Tung, Y.C.; Cardenas-Aguayo Mdel, C.; LaFerla, F.M.; Iqbal, K.; Grundke-Iqbal, I. Pharmacologic reversal
of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Abeta and tau pathologies in 3xTg-AD
mice. Acta Neuropathol. 2010, 120, 605–621. [CrossRef]
293. Kazim, S.F.; Iqbal, K. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: Emerging
therapeutic modality for Alzheimer’s disease. Mol. Neurodegener. 2016, 11, 50. [CrossRef]
294. Rockenstein, E.; Ubhi, K.; Doppler, E.; Novak, P.; Moessler, H.; Li, B.; Blanchard, J.; Grundke-Iqbal, I.; Iqbal, K.; Mante, M.;
et al. Regional comparison of the neurogenic effects of CNTF-derived peptides and cerebrolysin in AbetaPP transgenic mice. J.
Alzheimers Dis. 2011, 27, 743–752. [CrossRef]
295. Li, B.; Wanka, L.; Blanchard, J.; Liu, F.; Chohan, M.O.; Iqbal, K.; Grundke-Iqbal, I. Neurotrophic peptides incorporating
adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice. FEBS Lett. 2010, 584,
3359–3365. [CrossRef]
296. Bolognin, S.; Buffelli, M.; Puolivali, J.; Iqbal, K. Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic
compound. Neurobiol. Aging 2014, 35, 2134–2146. [CrossRef]