Upload
paul-s-donnelly
View
223
Download
0
Embed Size (px)
Citation preview
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 ofstructural 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 andother 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 ofDNA and neurotransmitters [5��].
(v) C opper has an important role in brain metabolismas 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
www.sciencedirect.com
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.
www.sciencedirect.com
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
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
www.sciencedirect.com
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.
www.sciencedirect.com
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
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
1. Dobson CM: Protein folding and misfolding. Nature 2003,426:884-890.
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.
5.��
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.
6.��
Gaggelli E, Kozlowski H, Valensin D, Valensin G: Copperhomeostasis and neurodegenerative disorders (Alzheimer’s,prion, and Parkinson’s diseases and amyotrophic lateralsclerosis). Chem Rev 2006, 106:1995-2044.
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.
8. Barnham KJ, Cappai R, Beyreuther K, Masters CL, Hill AF:Delineating common molecular mechanisms in Alzheimer’sand prion diseases. Trends Biochem Sci 2006, 31:465-472.
9. Gaeta A, Hider RC: The crucial role of metal ions inneurodegeneration: the basis for a promising therapeuticstrategy. Br J Pharmacol 2005, 146:1041-1059.
10.�
Valentine JS, Doucette PA, Potter SZ: Copper-zinc superoxidedismutase and amyotrophic lateral sclerosis.Annu Rev Biochem 2005, 74:563-593.
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.
12.�
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.
Current Opinion in Chemical Biology 2007, 11:128–133
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.
www.sciencedirect.com
Copper and Alzheimer’s disease Donnelly, Xiao and Wedd 133
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.
www.sciencedirect.com
40.��
Kessler H, Pajonk F-G, Meisser P, Schneider-Axmann T,Hoffmann K-H, Supprian T, Herrmann W, Obeid R, Multhaup G,Falkai P et al.: Cerebrospinal fluid diagnostic markerscorrelate with lower plasma copper and ceruloplasmin inpatients with Alzheimer’s disease. J Neural Transm 2006,113:1763-1769.
See annotation to [39��].
41. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD,McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y-S et al.:Treatment with a copper-zinc chelator markedly and rapidlyinhibits b-amyloid accumulation in Alzheimer’s diseasetransgenic mice. Neuron 2001, 30:665-676.
42. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M,MacGregor L, Kiers L, Cherny R, Li Q-X, Tammer A et al.: Metal-protein attenuation with iodochlorhydroxyquin (clioquinol)targeting Ab amyloid deposition and toxicity in Alzheimerdisease: a pilot phase 2 clinical trial. Arch Neurol 2003,60:1685-1691.
43.��
White AR, Du T, Laughton KM, Volitakis I, Sharples RA, Xilinas ME,Hoke DE, Holsinger RMD, Evin G, Cherny RA et al.: Degradationof the Alzheimer disease amyloid b-peptide by metal-dependent up-regulation of metalloprotease activity.J Biol Chem 2006, 281:17670-17680.
Metal complexes activated cell-signalling pathways that upregulatedmatrix metalloprotease enzymes capable of degrading the Ab peptide.
44. Dong J, Schokes JE, Scott RA, Lynn DG: Modulating amyloidself-assembly and fibril morphology with Zn(II).J Am Chem Soc 2006, 128:3540-3542.
45. Mercer JFB, Llanos RM: Molecular and cellular aspects ofcopper transport in developing mammals. J Nutr 2003,133:1481S-1484S.
46. Shim H, Harris ZL: Genetic defects in copper metabolism.J Nutr 2003, 133:1527S-1531S.
Current Opinion in Chemical Biology 2007, 11:128–133