Authors: Aso, Ester | Andrés-Benito, Pol | Carmona, Margarita | Maldonado, Rafael | Ferrer, Isidre
Article Type: Research Article
Abstract: The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9 -tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of …soluble Aβ40 . However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing. Show more
Keywords: AβPP/PS1 mice, Alzheimer’s disease, amyloid, cannabinoid receptor 2, cognitive impairment, Δ9-tetrahidrocannabinol and cannabidiol, tau, therapy
DOI: 10.3233/JAD-150913
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 489-500, 2016
Authors: Zafar, Saima | Shafiq, Mohsin | Younas, Neelam | Schmitz, Matthias | Ferrer, Isidre | Zerr, Inga
Article Type: Research Article
Abstract: Rapidly progressive Alzheimer’s disease (rpAD) is a variant of AD distinguished by a rapid decline in cognition and short disease duration from onset to death. While attempts to identify rpAD based on biomarker profile classifications have been initiated, the mechanisms which contribute to the rapid decline and prion mimicking heterogeneity in clinical signs are still largely unknown. In this study, we characterized prion protein (PrP) expression, localization, and interactome in rpAD, slow progressive AD, and in non-dementia controls. PrP along with its interacting proteins were affinity purified with magnetic Dynabeads Protein-G, and were identified using Q-TOF-ESI/MS analysis. Our data demonstrated …a significant 1.2-fold decrease in di-glycosylated PrP isoforms specifically in rpAD patients. Fifteen proteins appeared to interact with PrP and only two proteins3/4histone H2B-type1-B and zinc alpha-2 protein3/4were specifically bound with PrP isoform isolated from rpAD cases. Our data suggest distinct PrP involvement in association with the altered PrP interacting protein in rpAD, though the pathophysiological significance of these interactions remains to be established. Show more
Keywords: Aldolase A, Alzheimer’s disease, co-immunofluorescence, co-immunoprecipitation, histone, myelin P2, peroxiredoxin 1, prion, proteomics, synapsin, tubulin, zinc
DOI: 10.3233/JAD-170237
Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 265-275, 2017
Authors: Porquet, David | Griñán-Ferré, Christian | Ferrer, Isidre | Camins, Antoni | Sanfeliu, Coral | del Valle, Jaume | Pallàs, Mercè
Article Type: Research Article
Abstract: The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on …AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss. Show more
Keywords: AMPK, inflammation, mitochondria, resveratrol, sirtuin 1
DOI: 10.3233/JAD-140444
Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1209-1220, 2014
Authors: Martín, Virginia | Fabelo, Noemí | Santpere, Gabriel | Puig, Berta | Marín, Raquel | Ferrer, Isidre | Díaz, Mario
Article Type: Research Article
Abstract: Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyunsaturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer's disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes …(mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24–85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD. Show more
Keywords: Alzheimer's disease, docosahexaenoic acid, human brain cortex, lipid rafts, membrane phospholipids, polyunsaturated fatty acids
DOI: 10.3233/JAD-2010-1242
Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 489-502, 2010
Authors: Díaz, Mario | Fabelo, Noemí | Martín, Virginia | Ferrer, Isidre | Gómez, Tomás | Marín, Raquel
Article Type: Research Article
Abstract: In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface …and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3–32.0°C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp ) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that β-secretase/AβPP (amyloid-β protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AβPP. Show more
Keywords: BACE1, β-secretase, cerebellum, docosahexaenoic acid, entorhinal cortex, fluorescence anisotropy, frontal cortex, lipid rafts, membrane viscosity, polyunsaturated fatty acids
DOI: 10.3233/JAD-141146
Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1185-1198, 2015
Authors: Armand-Ugón, Mercedes | Aso, Ester | Moreno, Jesús | Riera-Codina, Miquel | Sánchez, Alex | Vegas, Esteban | Ferrer, Isidre
Article Type: Research Article
Abstract: Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer's disease. Groups of 5-month-old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 UI/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in …erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ) plaque burden and soluble Aβ40 . Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor α1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission. Show more
Keywords: AβPP/PS1 transgenic mice, Alzheimer's disease, amyloid-β, carbamylated erythropoietin, erythropoietin, neurotransmitter receptors
DOI: 10.3233/JAD-141389
Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 407-421, 2015
Authors: Huesa, Gema | Baltrons, María Antonia | Gómez-Ramos, Pilar | Morán, Asunción | García, Agustina | Hidalgo, Juan | Francés, Silvia | Santpere, Gabriel | Ferrer, Isidre | Galea, Elena
Article Type: Research Article
Abstract: RhoGTPases control cytoskeleton dynamics thereby modulating synaptic plasticity. Because Alzheimer's disease (AD) is characterized by synaptic dysfunction, we sought to determine whether the expression, activity, or localization of the GTPases RhoA, Rac1 and Cdc42, as well as p21-PAK, a downstream target of Rac1/Cdc42, were altered in 18-month-old AβPP Tg2576 mice (Swedish mutation) or in brains from patients with AD and, for comparison in the case of RhoA, Pick's disease (PiD), a neurodegenerative disorder characterized by hyper-phosphorylated tau accumulation. Immunohistochemical analyses revealed a distinct localization of each RhoGTPase in synapses, dendrite shafts, neuronal bodies, or astrocytes. The association of RhoA with …synapses and dendritic microtubules was confirmed by electron microscopy. In AβPP mice, RhoA expression decreased in synapses and increased in dystrophic neurites, suggesting altered subcellular targeting of RhoA. In AD, RhoA immunostaining decreased in the neuropil and markedly increased in neurons, co-localizing with hyperphosphorylated tau inclusions, as though RhoA were sequestered by neurofibrillary tangles. Additionally, total RhoA protein was lower in the AD brain hippocampus, reflecting loss of the membrane bound, presumably active, GTPase. RhoA colocalized with hyperphosphorylated tau in PiD, again suggesting that altered subcellular targeting of RhoA is related to neurodegeneration. No major immunohistochemical changes were observed for Rac1, Cdc42, or p21-PAK, thus identifying RhoA among RhoGTPases as a possible therapeutic target in AD. Show more
Keywords: Actin, cytoskeleton, microtubules, neurofibrillary tangles, Pick's disease, synaptic terminals, tau
DOI: 10.3233/JAD-2010-1203
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 37-56, 2010
Authors: Boada, Mercè | Anaya, Fernando | Ortiz, Pilar | Olazarán, Javier | Shua-Haim, Joshua R. | Obisesan, Thomas O. | Hernández, Isabel | Muñoz, Joan | Buendia, Mar | Alegret, Montserrat | Lafuente, Asunción | Tárraga, Lluís | Núñez, Laura | Torres, Mireia | Grifols, Joan Ramon | Ferrer, Isidre | Lopez, Oscar L. | Páez, Antonio
Article Type: Research Article
Abstract: Background: Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-β (Aβ) peptide between cerebrospinal fluid (CSF) and plasma compartments. Objective: To determine whether plasma exchange (PE) with albumin replacement was able to modify Aβ concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer’s disease (AD). Methods: In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein® , Grifols) with …three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Aβ1–40 and Aβ1–42 levels, as well as cognitive, functional, and behavioral measures were determined. Results: CSF Aβ1–42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus –45.5 pg/mL; 95% CI: –19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Aβ1–42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Aβ1–40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05). Conclusion: PE with human albumin modified CSF and plasma Aβ1–42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued. Show more
Keywords: Albumin, Alzheimer’s disease, CSF Aβ, plasma Aβ, plasma exchange
DOI: 10.3233/JAD-160565
Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 129-143, 2017
