6
Copper and Alzheimer’s disease Paul S Donnelly, Zhiguang Xiao and Anthony G Wedd Copper is essential for some of the enzymes that have a role in brain metabolism. Sophisticated mechanisms balance copper import and export to ensure proper nutrient levels (homeostasis) while minimizing toxic effects. Several neurodegenerative diseases including Alzheimer’s disease (AD) are characterized by modified copper homeostasis. This change seems to contribute either directly or indirectly to increased oxidative stress, an important factor in neuronal toxicity. When coupled to misfolded proteins, this modified copper homeostasis appears to be an important factor in the pathological progression of AD. Addresses School of Chemistry, University of Melbourne, Parkville, Victoria 3010, Australia and Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, Victoria 3010, Australia Corresponding author: Donnelly, Paul S ([email protected]) Current Opinion in Chemical Biology 2007, 11:128–133 This review comes from a themed issue on Bioinorganic chemistry Edited by William B Tolman and Catherine L Drennan Available online 14th February 2007 1367-5931/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cbpa.2007.01.678 Introduction A system that regulates and coordinates the activities of cells is essential for survival of multicellular organisms. For humans, the endocrine and nervous systems pro- vide the means of internal communication between cells. In particular, the central nervous system consists of the brain and spinal cord. Neurodegenerative dis- eases often involve the presence of misfolded protein that leads to neuronal damage and impaired cognitive function [1,2]. Metal ions and complexes have key roles in a broad range of processes essential for brain function [3]: (i) Sodium and potassium are of fundamental import- ance to neurotransmission, and selective ion chan- nels have been characterized. Lithium is used to manage bipolar disorder, although its mechanism of action is not understood in molecular detail. (ii) Calcium ions are responsible for the initiation of structural changes in proteins that elicit a variety of neurological processes. (iii) Zinc is a major regulator of synaptic transmission and other neuronal processes and appears in the synaptic cleft at concentrations >1 mM [4]. The overall zinc level in the brain is estimated to be about 150 mM[5 ]. (iv) Iron is involved in respiration and in the synthesis of DNA and neurotransmitters [5 ]. (v) Copper has an important role in brain metabolism as it is essential for the known enzymes CuZn superoxide dismutase (SOD1), ceruloplasmin, cytochrome c oxidase, tyrosinase and dopamine b-hydroxylase. Its level has been estimated at 100– 150 mM. The brain is isolated from the plasma by the blood brain barrier (BBB), which acts to protect it from fluctuating metal ion concentrations in the plasma. Control of internal metal levels is regulated by sophisticated trans- port mechanisms. Several neurodegenerative diseases are characterized by altered copper homeostasis. This appears to contribute either directly or indirectly to increased oxidative stress, an important factor in neuronal toxicity. This Opinion focuses on aspects of copper homeostasis in neurodegenerative diseases and in Alzheimer’s disease, in particular. The molecular causes of these diseases remain unknown. Neglect of the role of other metal ions is an undoubted oversimplification of multi-faceted dis- eases that affect an organ of bewildering complexity. Nonetheless, there are intriguing relationships between copper regulation, protein aggregation and the amyloid plaque formation associated with Alzheimer’s disease. The possible involvement of copper in other neurode- generative conditions are mentioned. Recent more detailed reviews are available [6 ,7 ,8,9,10 ,11,12 ]. Copper metabolism The recommended intake of copper for adults is 0.9 mg/ day with an upper limit of 10 mg/day [13]. A healthy human contains about 110 mg of copper with about 9 mg present in the brain [6 ]. Copper is toxic in excess or in ’free’ forms inside the cell because of its ability to promote uncontrolled formation of reactive species (such as H 2 O 2 ,O 2 and OH via Haber-Weiss and Fenton reactions) and to coordinate randomly with functional groups. The word free implies significant concentrations of Cu aq n+ (n = 1, 2) or equivalent species with labile ligands [14]. Biological systems have evolved regulation mechanisms that balance copper import and export to ensure proper Current Opinion in Chemical Biology 2007, 11:128–133 www.sciencedirect.com

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Page 1: Copper and Alzheimer's disease

Copper and Alzheimer’s diseasePaul S Donnelly, Zhiguang Xiao and Anthony G Wedd

Copper is essential for some of the enzymes that have a role in

brain metabolism. Sophisticated mechanisms balance copper

import and export to ensure proper nutrient levels

(homeostasis) while minimizing toxic effects. Several

neurodegenerative diseases including Alzheimer’s disease

(AD) are characterized by modified copper homeostasis. This

change seems to contribute either directly or indirectly to

increased oxidative stress, an important factor in neuronal

toxicity. When coupled to misfolded proteins, this modified

copper homeostasis appears to be an important factor in the

pathological progression of AD.

AddressesSchool of Chemistry, University of Melbourne, Parkville, Victoria 3010,

Australia and Bio21 Molecular Science and Biotechnology Institute, 30

Flemington Road, Parkville, Victoria 3010, Australia

Corresponding author: Donnelly, Paul S ([email protected])

Current Opinion in Chemical Biology 2007, 11:128–133

This review comes from a themed issue on

Bioinorganic chemistry

Edited by William B Tolman and Catherine L Drennan

Available online 14th February 2007

1367-5931/$ – see front matter

# 2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2007.01.678

IntroductionA system that regulates and coordinates the activities of

cells is essential for survival of multicellular organisms.

For humans, the endocrine and nervous systems pro-

vide the means of internal communication between

cells. In particular, the central nervous system consists

of the brain and spinal cord. Neurodegenerative dis-

eases often involve the presence of misfolded protein

that leads to neuronal damage and impaired cognitive

function [1,2]. Metal ions and complexes have key roles

in a broad range of processes essential for brain function

[3]:

(i) S

Curre

odium and potassium are of fundamental import-

ance to neurotransmission, and selective ion chan-

nels have been characterized. Lithium is used to

manage bipolar disorder, although its mechanism of

action is not understood in molecular detail.

(ii) C

alcium ions are responsible for the initiation of

structural changes in proteins that elicit a variety of

neurological processes.

nt Opinion in Chemical Biology 2007, 11:128–133

(iii) Z

inc is a major regulator of synaptic transmission and

other neuronal processes and appears in

the synaptic cleft at concentrations >1 mM [4]. The

overall zinc level in the brain is estimated to be about

150 mM [5��].

(iv) I ron is involved in respiration and in the synthesis of

DNA and neurotransmitters [5��].

(v) C opper has an important role in brain metabolism

as it is essential for the known enzymes

CuZn superoxide dismutase (SOD1), ceruloplasmin,

cytochrome c oxidase, tyrosinase and dopamine

b-hydroxylase. Its level has been estimated at 100–

150 mM.

The brain is isolated from the plasma by the blood brain

barrier (BBB), which acts to protect it from fluctuating

metal ion concentrations in the plasma. Control of

internal metal levels is regulated by sophisticated trans-

port mechanisms. Several neurodegenerative diseases are

characterized by altered copper homeostasis. This

appears to contribute either directly or indirectly to

increased oxidative stress, an important factor in neuronal

toxicity.

This Opinion focuses on aspects of copper homeostasis

in neurodegenerative diseases and in Alzheimer’s disease,

in particular. The molecular causes of these diseases

remain unknown. Neglect of the role of other metal ions

is an undoubted oversimplification of multi-faceted dis-

eases that affect an organ of bewildering complexity.

Nonetheless, there are intriguing relationships between

copper regulation, protein aggregation and the amyloid

plaque formation associated with Alzheimer’s disease.

The possible involvement of copper in other neurode-

generative conditions are mentioned. Recent more

detailed reviews are available [6��,7�,8,9,10�,11,12�].

Copper metabolismThe recommended intake of copper for adults is 0.9 mg/

day with an upper limit of 10 mg/day [13]. A healthy

human contains about 110 mg of copper with about 9 mg

present in the brain [6��]. Copper is toxic in excess or in

’free’ forms inside the cell because of its ability to

promote uncontrolled formation of reactive species (such

as H2O2, O2� and OH via Haber-Weiss and Fenton

reactions) and to coordinate randomly with functional

groups. The word free implies significant concentrations

of Cuaqn+ (n = 1, 2) or equivalent species with labile

ligands [14].

Biological systems have evolved regulation mechanisms

that balance copper import and export to ensure proper

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Page 2: Copper and Alzheimer's disease

Copper and Alzheimer’s disease Donnelly, Xiao and Wedd 129

Figure 1

Oversimplified model of copper transport in eurykotic cells such as hepatocytes, which receive much of the copper absorbed from the small

intestine [45,46]. Membrane pumps Ctr1 and ATP7B, and chaperones Ccs and Hah1 transport CuI. Ceruloplasmin transports CuII. Cytochrome c

oxidase (cyt ox) and superoxide dismutase are redox enzymes that employ the CuII/CuI couple. As well as loading ceruloplasmin with copper,

the trans-Golgi network inserts copper into many enzymes. The ATP7B pump performs two functions: it transports nutrient copper into the

trans-Golgi network and excess copper out of the cell (by trafficking to the cell membrane via membrane-bound vesicles).

nutrient levels while minimizing toxic effects [15]. To

this end, free copper concentrations in normal cells

appear to be controlled at very low levels, perhaps

less than one atom per cell [16]. The transport mechan-

isms use trafficking proteins that mobilize copper ions

specifically or eliminate them. Figure 1 provides a mini-

mal representation of the present knowledge of copper

transport in liver hepatocytes. Equivalent pathways exist

in other cells where the Menkes disease ATPase protein

(ATP7A; a homologue of the Wilson disease ATPase

protein [ATP7B] in Figure 1) performs the dual role of

ATP-powered transport of nutrient copper into the trans-

Golgi network and of excess copper out of the cell.

Entry of nutrient copper into the brain requires trans-

port across the BBB. Menkes disease is associated with

malfunction of the pump ATP7A and one consequence

is the loss of copper transport across the BBB, implicat-

ing the role of ATP7A in this function. In addition, the

plasma membrane pump Ctr1 (Figure 1) is responsible

for import of copper into neurons and astrocytes

[17,18,19�,20,21].

Figure 2

Sequences of the Ab peptides.

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However, the picture is by no means complete. Other

neuronal proteins also bind copper tightly. These include

the precursor protein associated with Alzheimer’s disease

and those associated with the prion diseases. Their mol-

ecular role incoppernutrition in the brain isnotunderstood.

Alzheimer’s disease: the precursor proteinand the Ab peptideAlzheimer’s disease (AD) is the most common form of

neurodegenerative dementia. The formation of senile

plaques precipitated in the brain is a pathological marker

of the disease [12�]. Their core element is an aggregated

form of an acid peptide molecule involving 39–43 amino

acid residues, which is termed the Ab peptide (Figure 2).

This peptide is generally accepted to be neurotoxic and,

as such, is a therapeutic target as well as a diagnostic

marker. The exact nature of its toxic form is unknown but

could involve a soluble species in equilibrium with the

plaques themselves [22].

The Ab peptide is derived from proteolytic cleavage of a

large transmembrane protein, the amyloid precursor

Current Opinion in Chemical Biology 2007, 11:128–133

Page 3: Copper and Alzheimer's disease

130 Bioinorganic chemistry

protein (APP). Why this normal cellular process becomes

increasingly less efficient in the ageing brain is not under-

stood but is under intense study [23]. APP might have a

role in copper homeostasis. APP-knockout mice have

elevated levels of copper in the cerebral cortex [24],

whereas APP-overexpressing mice have reduced brain

copper levels [25,26]. Copper binding to APP is suggested

to reduce the formation of Ab peptide in vitro [27].

APP has a cysteine-rich copper-binding domain (CuBD;

residues 124–189) in the N-terminal region that binds

CuII and effects its reduction to CuI. NMR peak broad-

ening experiments on an expressed form of this domain

are consistent with a four-coordinate CuII(N-His)2(O-

Tyr)(S-Met) centre (Figure 3a) [27]. The fact that APP

is extracellular suggests that the cysteine residues might

be oxidized and not available as ligands for copper. EPR

data indicate that this CuII site is distorted away from

square planar stereochemistry towards tetrahedral [27]. As

documented for type 1 copper centres in blue copper

proteins, such distortion favours reduction to the CuI form

by cellular reductants such as ascorbate or glutathione.

Figure 3

Proposed structures of CuII centres bound to APP and Ab peptides.

(a) Binding site in the copper binding domain (residues 124–189)

of APP [27]. (b) Initial binding site for the Ab peptide in solution [29].

(c) Binuclear model (featuring a bridging histidyl ligand) for

aggregation of Ab peptides [31��].

Current Opinion in Chemical Biology 2007, 11:128–133

The topology of the apo-CuBD domain features an a-

helix packed over a triple strand b-sheet. This is structu-

rally homologous to some copper chaperone proteins,

including Hah1, Ccs and the external domains of ATP7A

and ATP7B (Figure 1). However, these bind copper via

CuI(S-Cys)2 motifs and are intracellular whereas the

CuBD is extracellular. A preliminary X-ray crystallo-

graphic study of the APP fragment 133–189 containing

the CuBD is available [28].

Copper and the Ab peptideSeveral different forms of the Ab peptide (Figure 2) have

been studied. Ab(1–40) is the most soluble and so the

most popular form for in vitro study. The additional I and

A residues in Ab(1–42) impose lower solubility and might

have a significant influence on aggregation.

The cores of Alzheimic plaques consist of aggregated Ab

peptides and have been described as metal sinks because

of their high metal content: Cu, 0.44 mM; Zn, 1 mM; Fe,

1 mM. [29]. In vitro, each of these metals is capable of

inducing aggregation of the peptide [30], which has a high

affinity for Cu(II) and complexation results in altered

morphology of the aggregated Ab fibrils [30].

EPR spectra are consistent with a mononuclear model

CuII(N-His)3(O-Tyr) in soluble Ab(1–40) peptide mono-

mers (Figure 3b). However, for CuII centres in aggregated

peptide, spectra have been interpreted in terms of a

binuclear CuII model (featuring an anionic histidyl brid-

ging ligand) as an inherent component (Figure 3c)

[29,31��]. Such a bridging ligand is a feature of the

binuclear Cu–Zn centre in the superoxide dismutase

enzyme SOD1 (Figure 1). This binuclear model is pro-

posed to be the key component of Cu-Ab(1–42) solutions

that were toxic to cultured primary cortical neurons and

that correlated with increased levels of lipid peroxidation

and dityrosine (indicators of oxidative stress) [31��].

By contrast, EPR studies of CuII binding in both soluble

and fibrillar Ab(1–40) peptides were consistent with a

mononuclear metal site similar to that of Figure 3b [32].

The controversy continues as vibrational spectra were

interpreted with a mononuclear model featuring histidine

and deprotonated peptide amide ligands [33]. This model

was supported by recent NMR analysis of CuII-Ab(1–40)

solutions [34�]. It is likely that some of these contrasting

findings will be traced to differences in conditions, such as

the individual buffers used (TRIS pH 7.4 versus phosphate

pH 6.9, 7.3), the copper:peptide ratios and the source of

metal ion [31��]. These anomalies highlight the complexity

of the system and the importance of subtle yet crucial

structural factors. It is thought that the inflamed AD brain

has a pH lower than the normal physiological pH [6��].

CuII-Ab complexes catalyze the production of H2O2 from

O2. [35] This activity might be significant to oxidative

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Page 4: Copper and Alzheimer's disease

Copper and Alzheimer’s disease Donnelly, Xiao and Wedd 131

damage of neurons as H2O2 is capable of diffusing

through cell membranes and oxidizing intracellular

proteins and lipids. Perhaps more important is the ability

of the CuI-Ab complex to catalyse OH radical production

in the presence of H2O2 and cellular reductants (Fenton

chemistry). The creation of an environment of oxidative

stress via such chemistry might be compounded by a

functional deficiency of intracellular copper. Copper

bound in extracellular plaque deposits and/or interfer-

ence in copper trafficking pathways (Figure 1) might lead

to depleted intracellular copper levels. This would reduce

the activities of SOD1 and cytochrome oxidase in the

brain. A symbiotic process of increased oxidative stress

coupled with a reduction in key metabolic and defence

mechanisms could contribute significantly to neuronal

damage.

Copper and the treatment of Alzheimer’sdiseaseEmerging evidence suggests that AD might be character-

ized by copper deficiency as recent data indicate that AD

patients have higher levels of copper in the plasma but

lower levels in the brain [36��]. In a transgenic mouse

model of AD, an increase in neuronal copper levels

(induced either by genetic manipulation or by copper

supplementation of diet) led to a significant decrease in

brain Ab levels [36��,37,38]. In addition, a recent study of

33 patients revealed a negative correlation between plasma

copper levels and cognitive decline which was interpreted

in terms of a mild copper deficiency in most AD patients

[39��,40��]. Although the mechanism leading to these

changes is not understood, the observations led to the

suggestion that copper supplements might have thera-

peutic potential. A clinical trial of daily supplementation

via the salt CuII orotate is currently underway in Germany

(http://www.alzheimer-bayer.de/alzh._st1.html) [39��].

Clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline;

Figure 4) has received considerable recent attention as

it is both capable of crossing the BBB and acting as a

bidentate ligand for CuII (and other metal ions). In

preliminary in vitro studies, CQ rapidly dissolved Ab

aggregates (synthetic or derived from AD brains). Sub-

sequent studies revealed that a nine-week CQ oral treat-

ment of transgenic mice resulted in halving of the Ab

Figure 4

Structure of clioquinol CQ.

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levels and significantly increased Cu and Zn levels in the

brain [41].

A small human clinical trial demonstrated significant

slowing of cognitive decline in a subset of AD patients

together with a lowering of plasma Ab(1–42) peptide

levels [42]. The mechanism of action was suggested to

be metal sequestration resulting in dissolution of the

aggregate. More recent data indicated that CQ can act

by alternative pathways involving modulation of cellular

biometal metabolism, APP expression and Ab processing

[43��]. An implication is that CQ acts as a metal ionophore

overcoming the copper deficiencies inherent in AD. The

influence of MII(CQ)2 complexes upon Ab metabolism in

cultured Chinese ovary cells overexpressing APP was

investigated recently [43��]. Metal complexes MII(CQ)2

(M = Cu, Zn) were taken up by these cells, triggering

activation of phosphoinositol-3-kinase that, in turn,

induced phosphorylation of downstream target mol-

ecules. This cascade resulted in upregulation of matrix

metalloproteases and degradation of extracellular Ab

peptide.

Copper and other neurodegenerativediseasesA role for copper is implicated in the properties of the

precursor proteins of several other neurodegenerative

diseases. Twenty per cent of inherited cases of amyo-

trophic lateral sclerosis (ALS or motor neuron disease) is

linked to mutations in the gene for the superoxide dis-

mutase SOD1 (Figure 1). Some pathological precipitates

in this familial form of the disease show high proportions

of SOD1 [10�]. However, the SOD1-dependent form

constitutes only about 2% of total ALS cases.

The prion protein is found in high levels in neurons and is

the precursor for diseases such as scrapies (sheep), mad

cow disease (cattle) and Creutzfeldt-Jakob disease

(humans). It can bind 4–7 Cu2+ ions in sites including

the so-called octa-repeat region. The role that this prop-

erty might have in prion pathogenesis remains uncertain

but intriguing [6��,8,11].

The onset of Parkinson’s disease might be associated with

problems of copper metabolism and those of other bio-

metals [6��,12�].

ConclusionsBesides copper, other factors undoubtedly have a role in

the pathological progression of a disease as complex as

AD. Metals such as iron and zinc are also implicated but

have been neglected in this article [44]. In addition, a

multitude of other neurochemical interactions and

protein metabolic pathways can contribute to neurode-

generation. Despite these uncertainties, modified copper

homeostasis appears to be an important factor and is a

promising target for therapeutic strategies.

Current Opinion in Chemical Biology 2007, 11:128–133

Page 5: Copper and Alzheimer's disease

132 Bioinorganic chemistry

AcknowledgementsWe thank the Australian Research Council for financial support grantsDP0452845 (PSD) and DP0556854 (AGW). PSD thanks Kevin Barnham forcrucial contributions to their collaborative research.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

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2. Selkoe DJ: Folding proteins in fatal ways. Nature 2003,426:900-904.

3. Burdette SC, Lippard SJ: Meeting of the minds:metalloneurochemistry. Proc Natl Acad Sci USA 2003,100:3605-3610.

4. Frederickson CJ, Suh SW, Silva D, Frederickson CJ,Thompson RB: Importance of zinc in the central nervoussystem: the zinc-containing neuron. J Nutr 2000,130:1471S-1483S.

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White AR, Barnham KJ, Bush AI: Metal homeostasis inAlzheimer’s disease. Expert Rev Neurother 2006, 6:711-722.

Recent review that focuses on the proposed roles of iron, copper and zincin Alzheimer’s disease.

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Highly recommended review covering detailed molecular aspects of therole of copper in neurodegenerative diseases.

7.�

Sigel A, Sigel H, Sigel RKO (Eds): Neurodegenerative Diseases andMetal Ions: Metal Ions in Life Sciences, Vol 1. Wiley; 2006. Volumewhich contains 13 relevant articles.

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Up-to-date account of the molecular understanding of this condition.

11. Brown DR, Kozlowski H: Biological inorganic and bioinorganicchemistry of neurodegeneration based on prion andAlzheimer diseases. Dalton Trans 2004:1907-1917.

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Barnham KJ, Masters CL, Bush AI: Neurodegenerative diseasesand oxidative stress. Nat Rev Drug Discov 2004, 3:205-214.

The focus of this article is on the implications of oxidative stress in thebrain, the potential involvement of metal ions and possible therapeuticoptions.

13. Institute of Medicine, Food Nutrition Board: Dietary ReferenceIntakes for Vitamin A: Vitamin K, Arsenic, Boron, Chromium,Copper, Iodine, Iron, Manganese, Molybdenum, Nickel,Silicon, Vanadium, and Zinc Washington DC: National AcademyPress; 2000:, Chapter 7.

14. Finney LA, O’Halloran TV: Transition metal speciation in the cell:insights from the chemistry of metal ion receptors.Science 2003, 300:931-936.

15. Pena MMO, Lee J, Thiele DJ: A delicate balance: homeostaticcontrol of copper uptake and distribution. J Nutr 1999,129:1251-1260.

16. Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV:Undetectable intracellular free copper: the requirement of acopper chaperone for superoxide dismutase. Science 1999,284:805-808.

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17. Zhou B, Gitschier J: hCTR1: a human gene for copper uptakeidentified by complementation in yeast. Proc Natl Acad Sci USA1997, 94:7481-7486.

18. Kuo YM, Zhou B, Cosco D, Gitschier J: The copper transporterCTR1 provides an essential function in mammalianembryonic development. Proc Natl Acad Sci USA 2001,98:6836-6841.

19.�

Nose Y, Rees EM, Thiele DJ: Structure of the Ctr1 coppertrans‘PORE’ter reveals novel architecture. Trends Biochem Sci2006, 31:604-607.

This review summarizes the molecular aspects of a key copper trans-porter (cf, Figure 1).

20. Lee J, Prohaska JR, Dagenais SL, Glover TW, Thiele DJ: Isolationof a murine copper transporter gene, tissue specificexpression and functional complementation of a yeast coppertransport mutan. Gene 2000, 254:87-96.

21. Eisses JF, Kaplan JH: The mechanism of copper uptakemediated by human CTR1: a mutational analysis. J Biol Chem2005, 280:37159-37168.

22. Ali FEA, Barnham KJ, Barrow CJ, Separovic F: Metal-catalyzedoxidative damage and oligomerization of the amyloid-bpeptide of Alzheimer’s disease. Aust J Chem 2004,57:511-518.

23. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A: Opposingactivities protect against age-onset proteotoxicity.Science 2006, 313:1604-1610.

24. White AR, Reyes R, Mercer JFB, Camakaris J, Zheng H, Bush AI,Multhaup G, Beyreuther K, Masters CL, Cappai R: Copper levelsare increased in the cerebral cortex and liver of APP andAPLP2 knockout mice. Brain Res 1999, 842:439-444.

25. Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR,Beyreuther K, Masters CL, Bush AI, Li Q-X: Overexpression ofAlzheimer’s disease amyloid-b opposes the age-dependentelevations of brain copper and iron. J Biol Chem 2002,277:44670-44676.

26. Maynard CJ, Cappai R, Volitakis I, Cherny RA, Masters CL, Li Q-X,Bush AI: Gender and genetic background effects on brainmetal levels in APP transgenic and normal mice: Implicationsfor Alzheimer b-amyloid pathology. J Inorg Biochem 2006,100:952-962.

27. Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ,Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS et al.:Structure of the Alzheimer’s disease amyloid precursorprotein copper binding domain. J Biol Chem 2003,278:17401-17407.

28. Kong GK, Galatis D, Barnham KJ, Polekhina G, Adams JJ,Masters CL, Cappai R, Parker MW, McKinstry WJ: Crystallizationand preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein ofAlzheimer’s disease. Acta Crystallograph Sect F Struct Biol CrystCommun 2005, 61:93-95.

29. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K,Barrow CJ, Masters CL, Bush AI, Barnham KJ: Alzheimer’sdisease amyloid-b binds copper and zinc to generate anallosterically ordered membrane-penetrating structurecontaining superoxide dismutase-like subunits.J Biol Chem 2001, 276:20466-20473.

30. Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS,Beyreuther K, Tanzi RE, Masters CL, Bush AI: Aqueousdissolution of Alzheimer’s disease Ab amyloid deposits bybiometal depletion. J Biol Chem 1999, 274:23223-23228.

31.��

Smith DP, Smith DG, Curtain CC, Boas JF, Pilbrow JR,Ciccotosto GD, Lau T-L, Tew DJ, Perez K, Wade JD et al.:Copper-mediated amyloid-b toxicity is associated with anintermolecular histidine bridge. J Biol Chem 2006,281:15145-15154.

Discussion of possible reasons for conflicting interpretations of the natureof CuII sites in Ab peptide species in monomers and aggregates.

32. Karr JW, Kaupp LJ, Szalai VA: Amyloid-b binds Cu2+ in amononuclear metal ion binding site. J Am Chem Soc 2004,126:13534-13538.

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33. Miura T, Suzuki K, Kohata N, Takeuchi H: Metal binding modes ofAlzheimer’s amyloid b-peptide in insoluble aggregates andsoluble complexes. Biochemistry 2000, 39:7024-7031.

34.�

Hou L, Zagorski MG: NMR reveals anomalous copper(II) bindingto the amyloid Ab peptide of Alzheimer’s disease.J Am Chem Soc 2006, 128:9260-9261.

NMR study of CuII binding to native Ab(1-40) peptide. Earlier studies usedAb(1-16) or Ab(1-28) peptides.

35. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JDA,Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LEet al.: Cu(II) potentiation of Alzheimer Ab neurotoxicity.Correlation with cell-free hydrogen peroxide production andmetal reduction. J Biol Chem 1999, 274:37111-37116.

36.��

Bayer TA, Multhaup G: Involvement of amyloid b precursorprotein (AbPP) modulated copper homeostasis in Alzheimer’sdisease. J Alzheimers Dis 2005, 8:201-206.

Review of data suggesting that a deficiency of copper in the centralnervous system is related to AD progression.

37. Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V,Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J et al.:In vivo reduction of amyloid-b by a mutant copper transporter.Proc Natl Acad Sci USA 2003, 100:14193-14198.

38. Bayer TA, Schaefer S, Simons A, Kemmling A, Kamer T, Tepest R,Eckert A, Schuessel K, Eikenberg O, Sturchler-pierrat C et al.:Dietary Cu stabilizes brain superoxide dismutase 1 activityand reduces amyloid Ab production in APP23 transgenic mice.Proc Natl Acad Sci USA 2003, 100:14187-14192.

39.��

Pajonk F-G, Kessler H, Supprian T, Hamzei P, Bach D,Schweickhardt J, Herrmann W, Obeid R, Simons A, Falkai P et al.:Cognitive decline correlates with low plasma concentrationsof copper in patients with mild to moderate Alzheimer’sdisease. J Alzheimers Dis 2005, 8:23-27.

Articles [39��] and [40��] support the theory that a mild copper deficiencymight contribute to AD progression.

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40.��

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