Acta Pharm.

61 (2011) 1–14 Review

DOI: 10.2478/v10007-011-0006-6

Metal ions, Alzheimer’s disease and chelation therapy

ANA BUDIMIR In the last few years, various studies have been provid-
ing evidence that metal ions are critically involved in the
University of Zagreb pathogenesis of major neurological diseases (Alzheimer,
Faculty of Pharmacy and Biochemistry Parkinson). Metal ion chelators have been suggested as
10000 Zagreb, Croatia potential therapies for diseases involving metal ion im-
balance. Neurodegeneration is an excellent target for ex-
ploiting the metal chelator approach to therapeutics. In
contrast to the direct chelation approach in metal ion
overload disorders, in neurodegeneration the goal seems
to be a better and subtle modulation of metal ion homeo-
stasis, aimed at restoring ionic balance. Thus, moderate
chelators able to coordinate deleterious metals without
disturbing metal homeostasis are needed. To date, seve-
ral chelating agents have been investigated for their po-
tential to treat neurodegeneration, and a series of 8-hy-
droxyquinoline analogues showed the greatest potential
for the treatment of neurodegenerative diseases.
Keywords: metal ions, Alzheimer’s disease, neurodegene-
Accepted January 27, 2011 ration, metal chelators, chelation therapy

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease, clini-

cally characterized by memory and cognitive dysfunctions. It is primarily a disease of
old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects
about 35 million people worldwide today (3) and it is estimated to nearly double every
20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cau-
se and no cure for AD and these numbers makes finding a cure or rational treatment for
AD an urgent priority. Despite significant advances in understanding the neuropatho-
logical and neurochemical events taking place in AD, the etiopathogenesis of progres-
sive and mental cognitive dysfunction associated with aging remains largely unclear.
Pathologically, AD is characterized by neuronal degeneration. The brains of AD pa-
tients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or
senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tan-
gles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in
learning and memory and emotional behavior such as the entorhinal cortex, hippocam-

* Correspondence; e-mail: anab@pharma.hr

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

pus, basal forebrain and amygdale. Brain regions with plaques typically exhibit reduced
numbers of synapses, and neurites associated with the plaques are often damaged. Neu-
rons that use glutamate or acetylcholine as neurotransmitters appear to be particularly
affected, but neurons that produce serotonin and norepinephrine are also damaged.

Neurofibrillary tangles
Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-asso-
ciated proteins Tau, which exhibit hyperphosphorylation and severe oxidative modifica-
tions. Native Tau proteins possess between 352 and 441 amino acids (molecular weight
55 to 62 kDa). These Tau proteins are microtubule-associated proteins abundant in neu-
rons. They interact with tubulin to stabilize microtubules and to promote tubulin assem-
bly into microtubules. Hyperphosphorylation of Tau proteins at abnormal sites (serine
and threonine residues) can result in the self-assembly of tangles of paired helical fila-
ments and straight filaments (5, 6) in neurons undergoing degeneration, which are in-
volved in the pathogenesis of AD and other tauopathies. It has also been proposed that
Al(III) and Fe(III) cations, found within the neurofibrillary tangles, could be partially in-
volved in the polymerization processes of hyperphosphorylated Tau proteins (7–9).

Amyloid peptides
Extracellular proteic plaques are built up by fibrils (10), whose major components
are peptides known as b-amyloid (Ab), which range in length from 39 to 43 amino acids.
These amyloid peptides originate from sequential proteolytic cleavages (11, 12) of a co-
mmon precursor called Amyloid Precursor Protein (APP) (13). APP is a large glycopro-
tein of 695 to 770 amino acids that comprises three parts, the extracellular N-terminal re-
gion, a single hydrophobic transmembrane region and the cytoplasmic C-terminal do-
main. Overexpression of APP could lead to early AD forms (14). The amino acid sequen-
ce of the largest amyloid peptide Ab-(1–42) is given in Fig. 1 (15).

+
H3N-Asp1-Ala-Glu-Phe-Arg-His6-Asp-Ser8-Gly-Tyr10-Glu-Val-His13-His14-Gln-Lys-Leu-
Val-Phe-Phe-Ala-Glu-Asp-Val-Gly25-Ser-Asn-Lys28-Gly-Ala-Ile-Ile-Gly-Leu-Met35-Val-
38 40 41 42 –
Gly-Gly -Val-Val -Ile -Ala -COO

Fig. 1. Primary structure of Ab-(1–42). Hydrophobic membrane-derived portion shown in bold.

Ile-Ale – lost amino acid residue for Ab-(1–42) to Ab-(1–40). Hypothetical amino acids involved in
the binding of metal ions.

b-amyloid peptides have a tendency to aggregate in aqueous solution. Two major

forms identified in the amyloid deposits in AD brain are Ab-(1–40) and Ab-(1–42) (16).
The Ab-(1–40) isoform is the predominant soluble species in biological fluids (» 90 %),
while the less abundant in biological fluids but the predominant species found in plaque
deposits Ab-(1–42) has the highest propensity for aggregation and fibrillogenesis (17).
The relative abundance of Ab-(1–42) with respect to Ab-(1–40) reflects the fact that even
a small elongation (Ile-Ala) of the stretch of hydrophobic residues in the C-terminal re-
gion dramatically increases the tendency of this peptide to aggregate (18). The b-amy-
loid fibril formation is a rather complex process, which is not yet unraveled (Fig. 2). Im-

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

portantly, it is now accepted that Ab peptides are neurotoxic in micromolar concentrations

depending on their conformational states (19). Some studies have indeed proven that
oligomers are 10 times more toxic than fibrils, and 40 times than monomers. Other stud-
ies have shown that the soluble oligomeric forms of Ab are the most toxic species, rather
than the more aggregated fibrils or protofibrils (20).

Monomer Oligomer Protofibrils

(soluble) (soluble) (soluble)

Fibrillar aggregates Extended fibrils Shortfibrils

(insoluble) (partially soluble) (soluble)

Fig. 2. Postulated b-amyloid fibril assembly.

To explain the occurrence of amyloid deposits and of neurofibrillary tangles, two

hypotheses were proposed: (i) Amyloid cascade hypothesis: Neurodegeneration in AD be-
gins with abnormal processing of the amyloid precursor protein APP and results in the
production, aggregation and deposition of the amyloid b peptides. The amyloid cascade
may facilitate neurofibrillary tangle formation and cell death. (ii) Neuronal cytoskeletal de-
generation hypothesis: Cytoskeletal changes are the main events that lead to neurodegene-
ration in AD, as the hyperphosphorylation and aggregation of Tau proteins are related
to the activation of cell death processes.

METAL HOMEOSTASIS IN ALZHEIMER’S DISEASE

The brain is a specialized organ that requires metal ions for a number of important
cellular processes. As such, the brain contains a relatively high concentration of a num-
ber of transition metals such as Fe, Zn, and Cu where they take part in the neuronal ac-
tivity within the synapses (ZnII in particular) and ensure the function of various metallo-
proteins (cytochrome C-oxidase, Cu/Zn superoxyde dismutase...). Cells have therefore
developed a sophisticated machinery for controlling metal-ion homeostasis. However, a
breakdown of these mechanisms, or absorption of metals with no known biological func-
tion, alter the ionic balance and can result in a disease state, including several neurode-
generative disorders such as AD (21). Understanding the complex structural and func-
tional interactions of metal ions with the various intracellular and extracellular compo-
nents of the central nervous system, under normal conditions and during neurodegene-
ration, is essential for the development of effective therapies.
Many studies have shown that the most important biometals, i.e., copper, zinc, and
iron as well as nonphysiological aluminium are involved in AD. They are suggested to
have two distinct roles in the pathophysiology of AD: (i) aggregation of Ab peptide, and
(ii) production of reactive oxygen species induced by Ab.

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

Copper
A significant amount of literature has accrued on examining the role of copper in
the pathogenesis of AD (for recent review see ref. 22). One of the key findings emerging
from these studies is that there is an excess of copper in the extracellular space of the
brain (23). Studies by Lovell et al. (24) demonstrated high concentration of Cu in amy-
loid plaques (~400 mM) compared to the normal brain extracellular concentration of
0.2–1.7 mmol L–1. This accumulation of extracellular copper is likely to be mediated by
copper binding to the Ab peptide. Aggregation of Ab peptides is a central phenomenon
in AD. Although Ab peptides undergo spontaneous self-aggregation, it is clear from ex-
periments in vitro that Cu2+ affects aggregation behavior of Ab. The Cu-induced Ab agg-
regation is still controversial, as accelerating and inhibiting effects have been published,
which apparently depend on the experimental conditions such as pH, salt and metal con-
centrations (25, 26). It is suggested that, on one hand, Cu promotes amorphous aggre-
gates and, on the other, Cu reduces formation of fibrils (27). In addition, Cu binding to
Ab can result in production of hydrogen peroxide through reduction of Cu(II) to Cu(I)
and subsequent generation of a highly toxic hydroxyl radical through the Fenton reac-
tion. Consequently, a cascade of events related to oxidative stress and subsequent neu-
ronal death occurs (28).
In contrast to increased extracellular Cu levels, intracellular Cu levels appear to be
reduced in AD brain compared to controls (29). Moreover, the activity of several cupro-
enzymes is diminished in AD, including copper/zinc superoxide (30) and cytochrome c
oxidase (31). Additionally, interactions of copper with Tau peptide have been assumed
to induce the development of neurofibrillary tangles, one of the hallmarks of AD (32).

Zinc
The potential role of zinc in the pathology of AD (for recent review see ref. 33) was
emphasized by the finding of Zn enrichment within AD plaques and a Zn increase in
the neuropil of AD patients compared to controls (24). Zinc has a crucial role in Ab ag-
gregation, which is the most well-established contribution that zinc may have in AD pa-
thogenesis. Aggregation of Ab peptides into protease-resistant deposits can be rapidly
induced in the presence of zinc ions under physiological conditions in vitro (34, 35). Zn
binds to Ab in a monomeric and stoichiometric Zn-Ab complex, which is transiently sta-
ble prior to aggregation; the structure of the aggregates was described to be more amor-
phous, i.e., to contain less fibril (36). This activity may not be that of a neurotoxic modu-
lator but rather of a neuroprotective agent since Zn can alleviate Ab toxicity in cortical
cultures (37). The precise mechanism of the protective effect of zinc against Ab toxicity is
unclear; nevertheless, the possible mechanism may include competing with Cu (or iron)
for Ab binding. Binding of zinc to Ab changes its conformation to the extent that copper
ions cannot reach its metal binding sites. Preventing copper from interacting with Ab
may prevent the Cu-Ab induced formation of hydrogen peroxide and free radicals.
Recently, it has been shown that zinc can also accelerate the aggregation of a Tau
peptide, the major protein subunit of neurofibrillary tangles, under reducing conditions
(38). Zinc inhibited the formation of intramolecular disulphide bonds but promoted in-
termolecular bonds between key cysteine residues.

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

Iron
Iron is a redox active metal, and its contributions to AD pathology are still unclear.
Within AD plaques, iron accumulates to almost 3 times that of normal neuropil levels
(~ 1 mmol L–1 compared to ~ 350 mmol L–1 in a healthy control neuropil) (24). Despite
having a high concentration in AD plaques, Fe ions are not likely to interact directly
with Ab in vivo. Although in vitro studies indicate that Fe induces Ab aggregation (39),
Fe does not copurify with Ab extracted from plaques (40), unlike Cu and Zn ions, and is
found primarily complexed with ferritin in the plaque-associated neuritic processes.
Oxidative stress is one of the earliest events in AD and seems to be involved in the
onset, progression and pathogenesis of the disease (41). A variety of studies have de-
monstrated that iron plays a pivotal role in the oxidative damage observed in proteins,
lipids, sugars, and nucleic acid. Like Cu, Fe has been associated with free radical genera-
tion through the Fenton reaction, leading to the formation of a highly reactive hydroxyl
radical.
In addition, Fe was found to accumulate in neurons with neurofibrillary tangles
(42). Fe3+ has the ability to bind with hyperphosphorylated Tau and to induce its aggre-
gation in vitro, leading to the formation of neurofibrillary tangles in AD. This process
can be reversed by reduction of Fe3+ back to Fe2+ (8).

Aluminium
Aluminium is the most widely distributed metal in the environment and is widely
used in daily life, thus providing easy exposure to human beings. Al was first suspected
to be implicated in the progression of AD, when it was observed that intra-cerebral in-
jection of this element into rabbits induced the formation of neurofibrillary tangles (43,
44). Al(III) is known to localize at high concentrations in AD amyloid deposits, but stud-
ies aimed at determining if it is elevated in AD brains, have not achieved consensus. It
was reported that Al(III) can induce Ab aggregation, but the reported metal concentra-
tions have since been claimed to be significantly above physiological levels, and when
Ab was exposed to lower micromolar levels of aluminium, no Ab aggregation was in-
duced (45). Overall, it appears that although this element may be a contributing factor to
the neurodegeneration in AD, it does not appear to have a causative role.
Metal coordination properties of Ab have been investigated employing a wide ran-
ge of techniques such as nuclear magnetic resonance (NMR) spectroscopy, electron para-
magnetic resonance (EPR) spectroscopy, circular dichroism (CD) spectroscopy, and mass
spectrometry (MS) (46–48). These studies have suggested that the coordination of Cu(II)
and Zn(II) in Ab species could occur via three histidine residues (H6, H13, and H14) and
possibly another N-terminal residue or the peptide backbone.

METALS CHELATORS FOR THE TREATMENT OF ALZHEIMER’S DISEASE

The precise mechanisms responsible for triggering neurodegenerative AD remain

unclear and hinder ready identification of therapeutic targets for pharmaceutical deve-
lopment. However, there has been a growing interest in a number of pharmacological ap-

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

proaches to help slow down the rate of both cognitive and functional declines associated
with aging while maintaining a positive quality of life. One of the currently accepted hy-
potheses, the metal hypothesis of Alzheimer’s disease states that the interactions between
metal ions and Ab, as well as abnormal metal ion homeostasis, are connected with AD
neuropathogenesis (49–51). Based on this hypothesis, disruption of metal-Ab interactions
via metal chelation therapy has been proposed in order to reduce neurotoxicity of me-
tal-Ab species and restore metal ion homeostasis in the brain (52). However, in order to
be used as potential drugs in the treatment of neurodegenerative diseases, chelators
must have particular properties. They must have a low molecular weight, be poorly or
not charged to favor the blood brain barrier (BBB) crossing and stable. They must selec-
tively target certain metal ions, because a strong non-specific chelation would result in a
general depletion of metal ions, including those of metalloenzymes, which are essential.
Once the chelator is in the brain, the molecule must be able to complex the metal ions
present in excess in the aggregated proteins so as to allow their dissolution and elimina-
tion. Finally, successful treatment with any chelator requires low toxicity and minimum
side effects of the drug itself.
To date, several metal chelators have been used as agents for metal ion chelation
therapy in AD. Desferrioxamine B (Desferal®, Fig. 3) was the first compound used to
treat metal overload in the CNS and to dissolve amyloid aggregates. The use of this com-
pound significantly reduced the behavioral and cognitive declines of AD patients (53).
However, the use of this siderophore also led to various disadvantages: (i) its hydrophi-
lic and charged character disables the BBB crossing (ii) it is rapidly degraded in vivo, and
(iii) it causes significant side effects (anemia...) because of its strong affinity for Fe(III)
and other divalent cations.

O OH O O
H
(CH2 )5 N N (CH2) 5
N (CH2) 5 N N
H2N
H
OH O O OH

Fig. 3. Chemical structure of desferrioxamine B.

Several other chelating agents (Fig. 4) have been investigated for their potential to
treat neurodegeneration (54–59). The lipophilic metal chelator DP-109 significantly re-
duced amyloid pathology in brains of human amyloid b precursor protein transgenic
mice (59). Compound XH1, based on a novel »pharmacophore conjugation« concept, is a
bifunctional metal chelator containing a DTPA-based binding unit and 4-benzothiazole-
-2-yl-phenylamine-amyloid binding units. It was shown to specifically reduce APP pro-
tein expression in human SH-SY5Y neuroblastoma cells and to attenuate cerebral Ab
amyloid pathology in PS1/APP transgenic mice without inducing apparent toxicity and
behavior disturbances (57). Derivatives of a 14-membered saturated tetraamine have
also attracted some recent interest. Bicyclam analogue JKL169 (1,1’-xylyl bis-1,4,8,11 tetra-
azacyclotetradecane) was effective in reducing Cu levels in the brain cortex and was able
to maintain normal Cu levels in the blood, CSF and corpus callossum in rats (60).

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

N N
N N N

N N N N N
OH OH OH
OH OH
VK-28 HLA-20 MK-30

CO 2H
CO 2H CO2H
N
NH HN N N
H H
NH N N N
N HN
N O O N
NH HN
S S
JKL-169 XH-1

CO 2Na

C 18H 37 O O O O
O O O O C18H 37

DP-109
NaO2C

Fig. 4. Chemical structure of chelators tested in AD.

A series of 8-hydroxyquinoline analogues (VK-28, HLA-20 and MA-30) (Fig. 4) have

shown the greatest potential for the treatment of several neurodegenerative diseases (61)
and one of these compounds, clioquinol (PBT1, Fig. 5), reached the pilot phase II clinical
trial (62–66), which suggests that clioquinol improves cognition and lowers plasma lev-
els of Ab42 in some patients.
Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ) is a small, lipophilic and bioavai-
lable metal chelator that has been reported to efficiently cross the BBB (67) and dissolves
amyloid plaques of the brain, probably by removing metal ions from the structure (which
could allow restoring of their redistribution) (63, 66).
Originally, clioquinol was developed by Ciba-Geigy and was widely used as a safe
intestinal disinfectant until it was withdrawn from oral use in 1970 (68) after it was asso-
ciated with an epidemic of neurotoxicity in Japan known as subacute myelo-opticoneu-
ropathy. The mechanism of this toxicity has not been precisely defined. The current lead-
ing hypothesis is that clioquinol decreases cobalamin (vitamin B12) bioavailability, result-
ing in a deficiency state and a syndrome similar to subacute combined degeneration (69).
However, it was reported that, given safely under the conditions of controlled dosing
Cl

I N
OH

Fig. 5. Chemical structure of clioquinol, CQ.

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

and vitamin supplementation, episodes of subacute myelo-opticoneuropathy may be

avoided (63).
CQ binds Cu2+ and Zn2+ (2:1 ratio) in a square, planar arrangement (70, 71) with
moderate affinity (log K1 (Cu) = 12.5, log K2 (Cu) = 10.9, log K1 (Zn) = 8.5 and log K2 (Zn)
= 7.6) (72). In 1999, Ashley I. Bush and his co-workers have demonstrated that CQ dis-
solves synthetic Ab-Cu2+/Zn2+ aggregates and amyloid deposits from post-mortem AD
brain (73). Using APP2576 transgenic mice (in vivo model of AD), they have shown that
oral treatment with clioquinol markedly inhibited amyloid-b deposits (49 % decrease) in
the absence of any noticeable neurotoxicity. Moreover, the general health and body weight
parameters were significantly more stable in the tested animals (62). These findings we-
re recently reproduced by C. Grossi et al. (74). A phase II clinical trial further supports
the beneficial use of clioquinol in AD patients. In this trial, clioquinol was well tolerated,
significantly reduced cognitive decline, and lowered plasma Ab levels in clioquinol-trea-
ted patients compared to those receiving placebo (66). Conflicting hypotheses currently
exist of the possible mode of action of CQ and on its ability to interfere with the brain
metal metabolism. Unlike high-affinity chelators, at therapeutic doses clioquinol does not
cause excretion of metals. Findings of C. Grossi et al. (74), demonstrating a modest but
significant elevation of Zn2+ and Fe2+/3+ levels in the neocortex and of Cu2+ levels in the
hippocampus of CQ-treated TgCRND8 mice, support the hypothesis of CQ as an iono-
phore facilitating metal uptake in the brain tissue.
Prana Biotechnology, which developed clioquinol (PBT1), has suspended its deve-
lopment after discovering that the manufacturing process of PBT1 contained certain mu-
tagenic »di-iodo« PBT1 impurities that could not be reduced to an acceptable level. A
clioquinol related compound, PBT2 (Prana Biotechnolgy), also an 8-hydroxyquinoline
derivative but lacking the iodine atom, has completed the phase IIa trial in AD patients
(75). PBT2 prevents production of Ab oligomers, dissolves the existing Ab oligomers, and
enhances cognitive function in transgenic mice (76).
The exact mechanism of action of CQ and PBT2 is still uncertain, so further studies
are necessary to better evaluate the safety and effectiveness of CQ or PBT2 as a possible
medical treatment for AD.

CONCLUSIONS AND FUTURE PERSPECTIVES

The brain requires high metal ion concentrations to carry out its numerous essential
functions. However, triggered by unclear mechanisms, the metal ion homeostasis is se-
verely dysregulated in Alzheimer’s disease and abnormal levels of Cu(II), Zn(II) and
Fe(III) have been found. Consequently, the brain has a poor capacity to cope with the ox-
idative stress generated by the redox active Cu(II) and Fe(III) ions accumulated in Ab
aggregates. Faced with these neurological disorders, a number of therapeutic strategies
aimed at ameliorating or inhibiting Ab aggregation and induced ROS generation, inclu-
ding the use of antioxidants and metal chelators, are currently being investigated for their
possible application in AD therapy. Among the few chelators tested so far, clioquinol
was the first to reach the pilot phase II clinical trial, which demonstrates the applicabili-
ty of this exogenous metal chelator. Although the use of clioquinol has been suspended

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

in AD research, a new and promising oxine based analogue PBT2 is presently under de-
velopment, which clearly indicates that this strategy will be favored. Clioquinol and
other lipophilic and mild chelators based on phenanthrolines or N-aroyl-N’-picolinoyl
hydrazine binding units have shown a great potential in vitro or in vivo and pave the
way to the design and preparation of new drugs for AD therapy. Combining antioxidant
activity and binding functionality into a single drug would undoubtedly broaden the
chances of success in AD therapy.

REFERENCES

1. D. M. Skovronsky, V. M.-Y. Lee and J. Q. Trojanowski, Neurodegenerative diseases: New con-

cepts of pathogenesis and their therapeutic implications, Annu. Rev. Pathol. Mech. Dis. 1 (2006)
151–170; DOI: 10.1146/annurev.pathol.1.110304.100113.
2. R. Mayeux, Epidemiology of neurodegeneration, Annu. Rev. Neurosci. 26 (2003) 81–104; DOI:
10.1146/annurev.neuro.26.043002.094919.
3. C. P. Ferri, R. Sousa, E. Albanese, W. S. Ribeiro and M. Honyashiki, World Alzheimer Report 2009
– Executive Summary (Eds. M. Prince and J. Jadeson), Alzheimer’s Disease International, London
2009, pp. 1–22; http://www.alz.co.uk/adi/publications.html; access date: January 27, 2011.
4. F. M. LaFerla and S. Oddo, Alzheimer’s disease: Ab, tau and synaptic dysfunction, Trends Mol.
Med. 11 (2005) 170–176; DOI: 10.1016/j.molmed.2005.02.009.
5. M. Tolnay and A. Probst, Tau protein pathology in Alzheimer’s disease and related disorders,
Neuropathol. Appl. Neurobiol. 25 (1999) 171–187; DOI: 10.1046/j.1365-2990.1999.00182.x.
6. C. Ballatore, V. M.-Y. Lee and J. Q. Trojanowski, Tau-mediated neurodegeneration in Alzhei-
mer’s disease and related disorders, Nature Rev. Neurosci. 8 (2007) 663–672; DOI: 10.1038/nrn2194.
7. C. W. Scott, A. Fieles, L. A. Sygowski and C. B. Caputo, Aggregation of tau protein by alumi-
num, Brain Res. 628 (1993) 77–84; DOI: 10.1016/0006-8993(93)90940-O.
8. A. Yamamoto, R.-W. Shin, K. Hasegawa, H. Naiki, H. Sato, F. Yoshimasu and T. Kitamoto, Iron
(III) induces aggregation of hyperphosphorylated tau, and its reduction to iron (II) reverses
the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer ’s dis-
ease, J. Neurochem. 86 (2003) 1137–1147; DOI: 10.1046/j.1471-4159.2002.01061.x.
9. R.-W. Shin, T. P. A. Kruck, H. Murayama and T. Kitamoto, A novel trivalent cation chelator Fe-
ralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of
Alzheimer’s disease, Brain Res. 961 (2003) 139–146; DOI: 10.1016/S0006-8993(02)03893-3.
10. T. Lührs, C. Ritter, M. Adrian, D. Riek-Loher, B. Bohrmann, H. Döbeli, D. Schubert and R. Riek,
3D structure of Alzheimer’s amyloid-b (1–42) fibrils, Proc. Natl Acad. Sci. USA 102 (2005)
17342–17347; DOI: 10.1073/pnas.0506723102.
11. W. P. Esler and M. S. Wolfe, A portrait of Alzheimer secretases – new features and familiar
faces, Science 293 (2001) 1449–1454; DOI: 10.1126/science.1064638.
12. M. P. Mattson, Pathways towards and away from Alzheimer’s disease, Nature 430 (2004)
631–639; DOI: 10.1038/nature02621.
13. M. Shoji, T. Golde, J. Ghiso, T. Cheung, S. Estus, L. Shaffer, X. Cai, D. McKay, R. Tintner and B.
Frangione, Production of the Alzheimer amyloid beta protein by normal proteolytic processing,
Science 258 (1992) 126–129; DOI: 10.1126/science.1439760.
14. C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald and K. Beyreuther, Amy-
loid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl Acad. Sci. USA 82
(1985 ) 4245–4249; DOI: 10.1073/pnas.82.12.4245.

9
A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

15. B. Clippingdale, J. D. Wade and C. J. Barrow, The amyloid-b peptide and its role in Alzheimer’s
disease, J. Peptide Sci. 7 (2001) 227–249; DOI: 10.1002/psc.324.abs.
16. C. Vigo-Pelfrey, D. Lee, P. Keim, I. Lieberburg and D. B. Schenk, Amyloid peptide from human
cerebrospinal fluid, J. Neurochem. 61 (1993) 1965–1968; DOI: 10.1111/j.1471-4159.1993.tb09841.x.
17. P. Seubert, C. Vigo-Pelfrey, F. Esch, M. Lee, H. Dovey, D. Davis, S. Sinha, M. Schiossmacher, J.
Whaley, C. Swindlehurst, R. McCormack, R. Wolfert, D. Selkoe, I. Lieberburg and D. Schenk,
Isolation and quantification of soluble Alzheimer’s b-peptide from biological fluids, Nature 359
(1992) 325–327; DOI: 10.1038/359325a0.
18. J. T. Jarret, E. P. Berger and P. T. Lansbury, The C-terminus of the b protein is critical in amylo-
idogenesis, Ann. NY Acad. Sci. USA 695 (1993) 144–148; DOI: 10.1111/j.1749-6632.1993.tb23043.x.
19. A. Lorenzo and B. A. Yankner, Beta-amyloid neurotoxicity requires fibril formation and is inhibited
by congo red, Proc. Natl. Acad. Sci. USA 91 (1994 ) 12243–12247; DOI: 10.1073/pnas.91.25.12243.
20. J. Hardy and D. J. Selkoe, The amyloid hypothesis of Alzheimer’s disease: Progress and prob-
lems on the road to therapeutics, Science 297 (2002) 353–356; DOI: 10.1126/science.1072994.
21. H. Kozlowski, A. Janicka-Klos, J. Brasun, E. Gaggelli, D. Valensin and G. Valensin, Copper, iron,
and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, trans-
port, distribution and regulation), Coord. Chem. Rev. 253 (2009) 2665–2685; DOI: 10.1016/j.ccr.
2009.05.011.
22. Y. Hung, A. Bush and R. Cherny, Copper in the brain and Alzheimer’s disease, J. Biol. Inorg.
Chem. 15 (2010) 61–76; DOI: 10.1007/s00775-009-0600-y.
23. P. J. Crouch, K. J. Barnham, A. I. Bush and A. R. White, Therapeutic Treatments for Alzheimer’s
disease based on metal bioavailability, Drug News Perspect. 19 (2006) 469–474; DOI: 10.1358/dnp.
2006.19.8.1021492.
24. M. A. Lovell, J. D. Robertson, W. J. Teesdale, J. L. Campbell and W. R. Markesbery, Copper, iron
and zinc in Alzheimer’s disease senile plaques, J. Neurol. Sci. 158 (1998) 47–52; DOI: 10.1016/
S0022-510X(98)00092-6.
25. C. S. Atwood, R. D. Moir, X. Huang, R. C. Scarpa, N. M. E. Bacarra, D. M. Romano, M. A. Hart-
shorn, R. E. Tanzi and A. I. Bush, Dramatic aggregation of Alzheimer Ab by Cu(II) is induced
by conditions representing physiological acidosis, J. Biol. Chem. 273 (1998) 12817–12826; DOI:
10.1074/jbc.273.21.12817.
26. B. Raman, T. Ban, K.-I. Yamaguchi, M. Sakai, T. Kawai, H. Naiki and Y. Goto, Metal ion-depend-
ent effects of clioquinol on the fibril growth of an amyloid b peptide, J. Biol. Chem. 280 (2005 )
16157–16162; DOI: 10.1074/jbc.M500309200.
27. P. Faller, Copper and zinc binding to amyloid-b: Coordination, dynamics, aggregation, reacti-
vity and metal-ion transfer, ChemBioChem 10 (2009) 2837–2845; DOI: 10.1002/cbic.200900321.
28. C. Hureau and P. Faller, A[beta]-mediated ROS production by Cu ions: Structural insights,
mechanisms and relevance to Alzheimer’s disease, Biochimie 91 (2009) 1212–1217; DOI: 10.1016/
j.biochi.2009.03.013.
29. M. A. Deibel, W. D. Ehmann and W. R. Markesbery, Copper, iron, and zinc imbalances in se-
verely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress,
J. Neurol. Sci. 143 (1996) 137–142; DOI: 10.1016/S0022-510X(96)00203-1.
30. M. C. Boll, M. Alcaraz-Zubeldia, S. Montes and C. Rios, Free copper, ferroxidase and SOD1 ac-
tivities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neu-
rodegenerative diseases, Neurochem. Res. 33 (2008) 1717–1723; DOI: 10.1007/s11064-008-9610-3.
31. I. Maurer, S. Zierz and H. J. Moller, A selective defect of cytochrome c oxidase is present in
brain of Alzheimer disease patients, Neurobiol. Aging 21 (2000) 455–462; DOI: 10.1016/S0197-
-4580(00) 00112-3.

10
A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

32. Q. Ma, Y. Li, J. Du, H. Liu, K. Kanazawa, T. Nemoto, H. Nakanishi and Y. Zhao, Copper binding
properties of a tau peptide associated with Alzheimer’s disease studied by CD, NMR, and
MALDI-TOF MS, Peptides 27 (2006) 841–849; DOI: 10.1016/j.peptides.2005.09.002.
33. N. T. Watt, I. J. Whitehouse and N. M. Hooper, The role of zinc in Alzheimer’s disease, Int. J.
Alzheimer’s Dis. 2011 (2011) in press; DOI: 10.4061/2011/971021.
34. A. Bush, W. Pettingell, G. Multhaup, M. D. Paradis, J. Vonsattel, J. Gusella, K. Beyreuther, C.
Masters and R. Tanzi, Rapid induction of Alzheimer A beta amyloid formation by zinc, Science
265 (1994 ) 1464–1467; DOI: 10.1126/science.8073293.
35. K. H. Lim, Y. K. Kim and Y.-T. Chang, Investigations of the molecular mechanism of metal-in-
duced Ab (1–40) amyloidogenesis, Biochemistry 46 (2007) 13523–13532; DOI: 10.1021/bi701112z.
36. C. Talmard, L. Guilloreau, Y. Coppel, H. Mazarguil, and P. Faller, Amyloid-beta peptide forms
monomeric complexes with CuII and ZnII prior to aggregation, ChemBioChem 8 (2007) 163–165;
DOI: 10.1002/cbic.200600319.
37. M. P. Cuajungco and K. Y. Faget, Zinc takes the center stage: its paradoxical role in Alzheimer’s
disease, Brain Res. Rev. 41 (2003) 44–56; DOI: 10.1016/S0165-0173(02)00219-9.
38. Z.-Y. Mo, Y.-Z. Zhu, H.-L. Zhu, J.-B. Fan, J. Chen and Y. Liang, Low micromolar zinc accelerates
the fibrillization of human tau via bridging of Cys-291 and Cys-322, J. Biolog. Chem. 284 (2009)
34648–34657; DOI: 10.1074/jbc.M109.058883.
39. P. W. Mantyh, J. R. Ghilardi, S. Rogers, E. DeMaster, C. J. Allen, E. R. Stimson and J. E. Maggio,
Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of b-amy-
loid peptide, J. Neurochem. 61 (1993) 1171–1174; DOI: 10.1111/j.1471-4159.1993.tb03639.x.
40. C. Opazo, X. Huang, R. A. Cherny, R. D. Moir, A. E. Roher, A. R. White, R. Cappai, C. L. Mas-
ters, R. E. Tanzi, N. C. Inestrosa and A. I. Bush, Metalloenzyme-like activity of Alzheimer’s dis-
ease b-amyloid, J. Biol. Chem. 277 (2002) 40302–40308; DOI: 10.1074/jbc.M206428200.
41. D. G. Smith, R. Cappai and K. J. Barnham, The redox chemistry of the Alzheimer’s disease amy-
loid beta peptide, Biochim. Biophysi. Acta – Biomembranes 1768 (2007) 1976–1990; DOI: 10.2217/
14796708.2.4.397.
42. P. F. Good, D. P. Perl, L. M. Bierer and J. Schmeidler, Selective accumulation of aluminum and
iron in the neurofibrillary tangles of Alzheimer’s disease: A laser microprobe (LAMMA) study,
Ann. Neurol. 31 (1992) 286–292; DOI: 10.1002/ana.410310310.
43. I. Klatzo, H. Wisniewski and E. Streicher, Experimental production of neurofibrillary degenera-
tion: 1. Light microscopic observations, J. Neuropathol. Exp. Neurol. 24 (1965) 187–199; DOI: 10.1097/
00005072-196504000-00002.
44. R. D. Terry and C. Pena, Experimental production of neurofibrillary degeneration: 2. Electron
microscopy, phosphatase histochemistry and electron prose analysis, J. Neuropathol. Exp. Neurol.
24 (1965) 200–210; DOI: 10.1097/00005072-196504000-00003.
45. D. Drago, M. Bettella, S. Bolognin, L. Cendron, J. Scancar, R. Milacic, F. Ricchelli, A. Casini, L.
Messori, G. Tognon and P. Zatta, Potential pathogenic role of b-amyloid1-42-aluminum com-
plex in Alzheimer’s disease, Int. J. Biochem. Cell Biol. 40 (2008) 731–746; DOI: 10.1016/j.biocel.
2007.10.014.
46. A. Rauk, The chemistry of Alzheimer’s disease, Chem. Soc. Rev. 38 (2009) 2698–2715; DOI: 10.1039/
b807980n.
47. L. E. Scott and C. Orvig, Medicinal inorganic chemistry approaches to passivation and removal
of aberrant metal ions in disease, Chem. Rev. 109 (2009) 4885–4910; DOI: 10.1021/cr9000176.
48. J. A. Duce and A. I. Bush, Biological metals and Alzheimer’s disease: Implications for therapeu-
tics and diagnostics, Prog. Neurobiol. 92 (2010) 1–18; DOI: 10.1016/j.pneurobio.2010.04.003.
49. I. Bush and R. E. Tanzi, Therapeutics for Alzheimer’s disease based on the metal hypothesis,
Neurotherapeutics 5 (2008) 421–432; DOI: 10.1016/j.nurt.2008.05.001.

11
A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

50. A. Gaeta and R. C. Hider, The crucial role of metal ions in neurodegeneration: the basis for a
promising therapeutic strategy, Br. J. Pharmacol. 146 (2005) 1041–1059; DOI: 10.1038/sj.bjp.0706416.
51. P. Zatta, D. Drago, S. Bolognin and S. L. Sensi, Alzheimer’s disease, metal ions and metal ho-
meostatic therapy, Trends Pharmacol. Sci. 30 (2009) 346–355; DOI: 10.1016/j.tips.2009.05.002.
52. L. R. Perez and K. J. Franz, Minding metals: Tailoring multifunctional chelating agents for neu-
rodegenerative disease, Dalton Trans. 39 (2010) 2177–2187; DOI: 10.1039/b919237a.
53. D. R. C. McLachlan, T. P. A. Kruck, W. Kalow, D. F. Andrews, A. J. Dalton, M. Y. Bell and W. L.
Smith, Intramuscular desferrioxamine in patients with Alzheimer’s disease, Lancet 337 (1991)
1304–1308; DOI: 10.1016/0140-6736(91)92978-B.
54. R. A. Cherny, J. T. Legg, C. A. McLean, D. P. Fairlie, X. Huang, C. S. Atwood, K. Beyreuther, R.
E. Tanzi, C. L. Masters and A. I. Bush, Aqueous dissolution of Alzheimer’s disease abeta amy-
loid deposits by biometal depletion, J. Biol. Chem. 274 (1999) 23223–23228; DOI: 10.1074/jbc.274.
33.23223.
55. R. A. Cherny, K. J. Barnham, T. Lynch, I. Volitakis, Q.-X. Li, C. A. McLean, G. Multhaup, K.
Beyreuther, R. E. Tanzi, C. L. Masters and A. I. Bush, Chelation and intercalation: Complemen-
tary properties in a compound for the treatment of Alzheimer’s disease, J. Struct. Biol. 130 (2000)
209–216; DOI: 10.1006/jsbi.2000.4285.
56. C. Boldron, I. Van der Auwera, C. Deraeve, H. Gornitzka, S. Wera, M. Pitié, F. Van Leuven and
B. Meunier, Preparation of cyclo-phen-type ligands: Chelators of metal ions as potential thera-
peutic agents in the treatment of neurodegenerative diseases, ChemBioChem 6 (2005) 1976–1980;
DOI: 10.1002/cbic.200500220.
57. A. Dedeoglu, K. Cormier, S. Payton, K. A. Tseitlin, J. N. Kremsky, L. Lai, X. Li, R. D. Moir, R. E.
Tanzi, A. I. Bush, N. W. Kowall, J. T. Rogers and X. Huang, Preliminary studies of a novel bifunc-
tional metal chelator targeting Alzheimer’s amyloidogenesis, Exp. Gerontol. 39 (2004) 1641–1649;
DOI: 10.1016/j.exger.2004.08.016.
58. Z. Cui, P. R. Lockman, C. S. Atwood, C.-H. Hsu, A. Gupte, D. D. Allen and R. J. Mumper, Novel
D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer’s and other
CNS diseases, Eur. J. Pharm. Biopharm. 59 (2005) 263–272; DOI: 10.1016/j.ejpb.2004.07.009.
59. J.-Y. Lee, J. E. Friedman, I. Angel, A. Kozak and J.-Y. Koh, The lipophilic metal chelator DP-109
reduces amyloid pathology in brains of human [beta]-amyloid precursor protein transgenic
mice, Neurobiol. Aging 25 (2004) 1315–1321; DOI: 10.1016/j.neurobiolaging.2004.01.005.
60. V. Moret, Y. Laras, N. Pietrancosta, C. Garino, G. Quelever, A. Rolland, B. Mallet, J. C. Norreel
and J. L. Kraus, 1,1 '-Xylyl bis-1,4,8,11-tetraaza cyclotetradecane: A new potential copper che-
lator agent for neuroprotection in Alzheimer’s disease. Its comparative effects with clioquinol
on rat brain copper distribution, Bioorg. Med. Chem. Lett. 16 (2006) 3298–3301; DOI: 10.1016/j.
bmcl.2006.03.026.
61. H. Zheng, S. Gal, L. M. Weiner, O. Bar-Am, A. Warshawsky, M. Fridkin and M. B. H. Youdim,
Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for
neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide
formation and monoamine oxidase inhibition, J. Neurochem. 95 (2005) 68–78; DOI: 10.1111/j.1471-
-4159.2005.03340.x.
62. D. Kaur, F. Yantiri, S. Rajagopalan, J. Kumar, J. Q. Mo, R. Boonplueang, V. Viswanath, R. Jacobs,
L. Yang, M. F. Beal, D. DiMonte, I. Volitaskis, L. Ellerby, R. A. Cherny, A. I. Bush and J. K. An-
dersen, Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo:
A novel therapy for Parkinson’s disease, Neuron 37 (2003) 899–909; DOI: 10.1016/S0896-6273
(03)00126-0.
63. R. A. Cherny, C. S. Atwood, M. E. Xilinas, D. N. Gray, W. D. Jones, C. A. McLean, K. J. Barnham,
I. Volitakis, F. W. Fraser, Y.-S. Kim, X. Huang, L. E. Goldstein, R. D. Moir, J. T. Lim, K. Beyreu-
ther, H. Zheng, R. E. Tanzi, C. L. Masters and A. I. Bush, Treatment with a copper-zinc chelator

12
A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

markedly and rapidly inhibits [beta]-amyloid accumulation in Alzheimer’s disease transgenic

mice, Neuron 30 (2001) 665–676; DOI: 10.1016/S0896-6273(01)00317-8.
64. H. Zheng, M. B. H. Youdim, L. M. Weiner and M. Fridkin, Synthesis and evaluation of peptidic
metal chelators for neuroprotection in neurodegenerative diseases, J. Pept. Res. 66 (2005)
190–203; DOI: 10.1111/j.1399-3011.2005.00289.x.
65. C. Deraeve, M. Pitie, H. Mazarguil and B. Meunier, Bis-8-hydroxyquinoline ligands as potential
anti-Alzheimer agents, New J. Chem. 31 (2007) 193–195; DOI: 10.1039/b616085a.
66. C. W. Ritchie, A. I. Bush, A. Mackinnon, S. Macfarlane, M. Mastwyk, L. MacGregor, L. Kiers, R.
Cherny, Q.-X. Li, A. Tammer, D. Carrington, C. Mavros, I. Volitakis, M. Xilinas, D. Ames, S. Da-
vis, K. Beyreuther, R. E. Tanzi and C. L. Masters, Metal-protein attenuation with iodochlorhy-
droxyquin (clioquinol) targeting Ab amyloid deposition and toxicity in Alzheimer disease: A
pilot phase 2 clinical trial, Arch. Neurol. 60 (2003) 1685–1691; DOI: 10.1001/archneur.60.12.1685.
67. A. I. Bush, Metal complexing agents as therapies for Alzheimer’s disease, Neurobiol. Aging 23
(2002) 1031–1038. DOI: 10.1016/S0197-4580(02)00120-3.
68. J. Tateishi, Subacute myelo-optico-neuropathy: Clioquinol intoxication in humans and animals,
Neuropathology 20 (Suppl.) S20–S24; DOI: 10.1046/j.1440-1789.2000.00296.x.
69. M. S. Yassin, J. Ekblom, M. Xilinas, C. G. Gottfries and L. Oreland, Changes in uptake of vita-
min B-12 and trace metals in brains of mice treated with clioquinol, J. Neurol. Sci 173 (2000) 40–44;
DOI: 10.1016/S0022-510X(99)00297-X.
70. M. Di Vaira, C. Bazzicalupi, P. Orioli, L. Messori, B. Bruni and P. Zatta, Clioquinol, a drug for
Alzheimer’s disease specifically interfering with brain metal metabolism: Structural character-
ization of its zinc(II) and copper(II) complexes, Inorg. Chem. 43 (2004) 3795–3797; DOI: 10.1021/
ic0494051.
71. C. C. Wagner, S. Calvo, M. H. Torre and E. J. Baran, Vibrational spectra of clioquinol and its
Cu(II) complex, J. Raman Spectrosc. 38 (2007) 373–376; DOI: 10.1002/jrs.1654.
72. A. Budimir, N. Humbert, M. Elhabiri, I. Osinska, M. Birus and A.-M. Albrecht-Gary, Hydroxy-
quinoline based binders: Promising ligands for chelatotherapy?, J. Inorg. Biochem, in press; DOI:
10.1016/j.jinorgbio.2010.08.014.
73. R. A. Cherny, J. T. Legg, C. A. McLean, D. P. Fairlie, X. Huang, C. S. Atwood, K. Beyreuther, R.
E. Tanzi, C. L. Masters and A. I. Bush, Aqueous dissolution of Alzheimer’s disease Ab amyloid
deposits by biometal depletion, J. Biol. Chem. 274 (1999) 23223–23228; DOI: 10.1074/jbc.274.33.
23223.
74. C. Grossi, S. Francese, A. Casini, M. C. Rosi, I. Luccarini, A. Fiorentini, C. Gabbiani, L. Messori,
G. Moneti and F. Casamenti, Clioquinol decreases amyloid-b burden and reduces working me-
mory impairment in a transgenic mouse model of Alzheimer’s disease, J. Alzheimer’s Dis. 17
(2009) 423–440.
75. L. Lannfelt, K. Blennow, H. Zetterberg, S. Batsman, D. Ames, J. Harrison, C. L. Masters, S. Tar-
gum, A. I. Bush, R. Murdoch, J. Wilson and C. W. Ritchie, Safety, efficacy, and biomarker find-
ings of PBT2 in targeting Ab as a modifying therapy for Alzheimer’s disease: a phase IIa, dou-
ble-blind, randomised, placebo-controlled trial, Lancet Neurol. 7 (2008) 779–786; DOI: 10.1016/
S1474-4422(08)70167-4.
76. P. A. Adlard, R. A. Cherny, D. I. Finkelstein, E. Gautier, E. Robb, M. Cortes, I. Volitakis, X. Liu, J.
P. Smith, K. Perez, K. Laughton, Q.-X. Li, S. A. Charman, J. A. Nicolazzo, S. Wilkins, K. Deleva,
T. Lynch, G. Kok, C. W. Ritchie, R. E. Tanzi, R. Cappai, C. L. Masters, K. J. Barnham and A. I.
Bush, Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline
analogs is associated with decreased interstitial Ab, Neuron 59 (2008) 43–55; DOI: 10.1016/j.neu-
ron.2008.06.018.

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A. Budimir: Metal ions, Alzheimer’s disease and chelation therapy, Acta Pharm. 61 (2011) 1–14.

S A @ E TA K

Kovinski ioni, Alzheimerova bolest i kelacijska terapija

ANA BUDIMIR

Najnovija istra`ivanja na polju neurodegeneracije jasno pokazuju da kovinski ioni

imaju zna~ajnu ulogu u patogenezi Alzheimerove kao i drugih neurodegenerativnih bo-
lesti. U skladu s ovim spoznajama upotreba kovinskih kelatora predstavlja zanimljiv i
inovativan farmakolo{ki pristup daljnjem istra`ivanju i mogu}oj terapiji neurodegenera-
tivnih stanja. U ovom radu ukratko je dan sa`etak istra`ivanja upotrebe kovinskih kela-
tora u tretmanu Alzheimerove bolesti s posebnim osvrtom na istra`ivanja analoga 8-hi-
droksikinolina.

Klju~ne rije~i: kovinski ioni, Alzheimerova bolest, neurodegeneracija, kovinski kelatori, kelacijska
terapija

Sveu~ili{te u Zagrebu, Farmaceutsko-biokemijski fakultet, Zagreb

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