Role of amyloid-β-metal interactions in Alzheimers disease

Future Neurology

Volumn 6, Issue 5, 2011, Pages 641-659

  Duce, James A ^a,b   Bush, Ashley I ^a,b   Adlard, Paul A ^a,b  

^a FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Alzheimer's disease; amyloid b precursor protein; cognition; copper; iron; therapy; zinc

Indexed keywords

ALPHA SECRETASE; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; BETA SECRETASE; BETA SECRETASE 1; CLIOQUINOL; COPPER; COPPER SULFATE; CURCUMIN; CYANOCOBALAMIN; DEFEROXAMINE; DP 109; EPIGALLOCATECHIN; FOLIC ACID; GAMMA SECRETASE; GINKGO BILOBA EXTRACT; GLYCOGEN SYNTHASE KINASE 3BETA; IRON; NEUROPROTECTIVE AGENT; OROTATE COPPER; PBT 2; PENICILLAMINE; PLACEBO; PRESENILIN; PYRROLIDINE DITHIOCARBAMATE; REAZIN; UNCLASSIFIED DRUG; ZINC;

5' UNTRANSLATED REGION; ABSENCE OF SIDE EFFECTS; ALZHEIMER DISEASE; AMYLOID PLAQUE; BINDING AFFINITY; BINDING SITE; CARBOXY TERMINAL SEQUENCE; COVALENT BOND; DIET SUPPLEMENTATION; DIETARY INTAKE; DRUG DOSE ESCALATION; DRUG MEGADOSE; ENDOCYTOSIS; ENTORHINAL CORTEX; GENE EXPRESSION; HIPPOCAMPUS; HUMAN; LOW DRUG DOSE; METAL BINDING; NONHUMAN; OXIDATIVE STRESS; PARIETAL CORTEX; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN CLEAVAGE; PROTEIN DEFECT; PROTEIN DEGRADATION; PROTEIN INTERACTION; PROTEIN PROCESSING; REVIEW; SINGLE DRUG DOSE; UNSPECIFIED SIDE EFFECT;

EID: 80052308785     PISSN: 14796708     EISSN: 17486971     Source Type: Journal    
DOI: 10.2217/fnl.11.43     Document Type: Review

References (181)

1. Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, Camakaris J. Copper depletion down-regulates expression of the Alzheimer's disease amyloid-b precursor protein gene. J. Biol. Chem. 279(19), 20378-20386 (2004).
2. Armendariz AD, Gonzalez M, Loguinov AV, Vulpe CD. Gene expression profiling in chronic copper overload reveals upregulation of Prnp and App. Physiol. Genomics 20(1), 45-54 (2004).
3. Cater MA, McInnes KT, Li QX et al. Intracellular copper deficiency increases amyloid-b secretion by diverse mechanisms. Biochem. J. 412(1), 141-152 (2008).
4. White AR, Reyes R, Mercer JF et al. Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res. 842(2), 439-444 (1999).
5. Bellingham SA, Ciccotosto GD, Needham BE et al. Gene knockout of amyloid precursor protein and amyloid precursor-like protein-2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts. J. Neurochem. 91(2), 423-428 (2004).
6. Phinney AL, Drisaldi B, Schmidt SD et al. In vivo reduction of amyloid-b by a mutant copper transporter. Proc. Natl Acad. Sci. USA 100(24), 14193-14198 (2003).
7. Maynard CJ, Cappai R, Volitakis I et al. Overexpression of Alzheimer's disease amyloid-b opposes the age-dependent elevations of brain copper and iron. J. Biol. Chem. 277(47), 44670-44676 (2002).
8. Bayer TA, Schafer S, Simons A et al. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Ab production in APP23 transgenic mice. Proc. Natl Acad. Sci. USA 100(24), 14187-14192 (2003).
9. Venti A, Giordano T, Eder P et al. The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5́-untranslated region. Ann. NY Acad. Sci. 1035, 34-48 (2004).
10. Rogers JT, Randall JD, Cahill CM et al. An iron-responsive element type II in the 5́-untranslated region of the Alzheimer's amyloid precursor protein transcript. J. Biol. Chem. 277(47), 45518-45528 (2002).
11. Takahashi M, Dore S, Ferris CD et al. Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease. Neuron 28(2), 461-473 (2000).
12. Duce JA, Tsatsanis A, Cater MA et al. Iron-export ferroxidase activity of b-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142(6), 857-867 (2010). nn Demonstrates that the amyloid-b precursor protein possesses ferroxidase activity that is inhibited by zinc. The abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in Alzheimer's disease (AD).
13. Valensin D, Mancini FM, Luczkowski M et al. Identification of a novel high affinity copper binding site in the APP145-155 fragment of amyloid precursor protein. Dalton Trans. (1), 16-22 (2004).
14. Simons A, Ruppert T, Schmidt C et al. Evidence for a copper-binding superfamily of the amyloid precursor protein. Biochemistry 41(30), 9310-9320 (2002).
15. Hesse L, Beher D, Masters CL, Multhaup G. The b A4 amyloid precursor protein binding to copper. FEBS Lett. 349(1), 109-116 (1994).
16. Barnham KJ, McKinstry WJ, Multhaup G et al. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J. Biol. Chem. 278(19), 17401-17407 (2003).
17. Atwood CS, Scarpa RC, Huang X et al. Characterization of copper interactions with alzheimer amyloid b peptides: Identification of an attomolar-affinity copper binding site on amyloid b1-42. J. Neurochem. 75(3), 1219-1233 (2000).
18. Bush AI, Pettingell WH Jr., Paradis MD, Tanzi RE. Modulation of Ab adhesiveness and secretase site cleavage by zinc. J. Biol. Chem. 269(16), 12152-12158 (1994).
19. Bush AI, Pettingell WH, Multhaup G et al. Rapid induction of Alzheimer Ab amyloid formation by zinc. Science 265(5177), 1464-1467 (1994). nn Clearly demonstrates a role for zinc in amyloid formation, and hence in the pathogenesis of AD. This work was critical in fostering this new area of reasearch into the novel (metal-mediated) causes and potential treatments for AD.
20. Bush AI, Pettingell WH Jr., de Paradis M, Tanzi RE, Wasco W. The amyloid b-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J. Biol. Chem. 269(43), 26618-26621 (1994).
21. Bush AI, Multhaup G, Moir RD et al. A novel zinc(II) binding site modulates the function of the b A4 amyloid protein precursor of Alzheimer's disease. J. Biol. Chem. 268(22), 16109-16112 (1993).
22. Bolognin S, Messori L, Drago D, Gabbiani C, Cendron L, Zatta P. Aluminum, copper, iron and zinc differentially alter amyloid-Ab1-42 aggregation and toxicity. Int. J. Biochem. Cell Biol. 43(6), 877-885 (2011).
23. Wan L, Nie G, Zhang J et al. b-amyloid peptide increases levels of iron content and oxidative stress in human cell and caenorhabditis elegans models of Alzheimer disease. Free Radic. Biol. Med. 50(1), 122-129 (2011).
24. Treiber C, Simons A, Strauss M et al. Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. J. Biol. Chem. 279(50), 51958-51964 (2004).
25. Acevedo KM, Hung YH, Dalziel AH et al. Copper promotes the trafficking of the amyloid precursor protein. J. Biol. Chem. 286(10), 8252-8262 (2011).
26. Ciuculescu ED, Mekmouche Y, Faller P. Metal-binding properties of the peptide APP170-188: A model of the ZnII-binding site of amyloid precursor protein (APP). Chemistry 11(3), 903-909 (2005).
27. Scheuermann S, Hambsch B, Hesse L et al. Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease. J. Biol. Chem. 276(36), 33923-33929 (2001).
28. Multhaup G, Ruppert T, Schlicksupp A et al. Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide. Biochemistry 37(20), 7224-7230 (1998).
29. Multhaup G, Bush AI, Pollwein P, Masters CL. Interaction between the zinc (II) and the heparin binding site of the Alzheimer's disease b A4 amyloid precursor protein (APP). FEBS Lett. 355(2), 151-154 (1994).
30. Danielsson J, Pierattelli R, Banci L, Graslund A. High-resolution NMR studies of the zinc-binding site of the Alzheimer's amyloid b-peptide. FEBS J. 274(1), 46-59 (2007).
31. Syme CD, Viles JH. Solution 1H NMR investigation of Zn2+ and Cd2+ binding to amyloid-b peptide (Ab) of Alzheimer's disease. Biochim. Biophys. Acta 1764(2), 246-256 (2006).
32. Karr JW, Szalai VA. Cu(II) binding to monomeric, oligomeric, and fibrillar forms of the Alzheimer's disease amyloid-b peptide. Biochemistry 47(17), 5006-5016 (2008).
33. Syme CD, Nadal RC, Rigby SE, Viles JH. Copper binding to the amyloid-b (Ab) peptide associated with Alzheimer's disease: Folding, coordination geometry, pH dependence, stoichiometry, and affinity of Ab1-28: Insights from a range of complementary spectroscopic techniques. J. Biol. Chem. 279(18), 18169-18177 (2004).
34. Chen WT, Liao YH, Yu HM, Cheng IH, Chen YR. Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-b stability, oligomerization, and aggregation: Amyloid-b destabilization promotes annular protofibril formation. J. Biol. Chem. 286(11), 9646-9656 (2011).
35. Shearer J, Szalai VA. The amyloid-b peptide of Alzheimer's disease binds Cu(I) in a linear bis-his coordination environment: Insight into a possible neuroprotective mechanism for the amyloid-b peptide. J. Am. Chem. Soc. 130(52), 17826-17835 (2008).
36. Himes RA, Park GY, Siluvai GS, Blackburn NJ, Karlin KD. Structural studies of copper(I) complexes of amyloid-b peptide fragments: Formation of two-coordinate bis(histidine) complexes. Angew. Chem. Int. Ed. Engl. 47(47), 9084-9087 (2008).
37. Hureau C, Balland V, Coppel Y, Solari PL, Fonda E, Faller P. Importance of dynamical processes in the coordination chemistry and redox conversion of copper amyloid-b complexes. J. Biol. Inorg. Chem. 14(7), 995-1000 (2009).
38. Curtain CC, Ali F, Volitakis I et al. Alzheimer's disease amyloid-b binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 276(23), 20466-20473 (2001).
39. Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ. Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-b peptide with membrane lipid. J. Biol. Chem. 278(5), 2977-2982 (2003).
40. Mekmouche Y, Coppel Y, Hochgrafe K et al. Characterization of the ZnII binding to the peptide amyloid-b1-16 linked to Alzheimer's disease. Chembiochem 6(9), 1663-1671 (2005).
41. Drew SC, Noble CJ, Masters CL, Hanson GR, Barnham KJ. Pleomorphic copper coordination by Alzheimer's disease amyloid-b peptide. J. Am. Chem. Soc. 131(3), 1195-1207 (2009).
42. Dorlet P, Gambarelli S, Faller P, Hureau C. Pulse EPR spectroscopy reveals the coordination sphere of copper(II) ions in the 1-16 amyloid-b peptide: A key role of the first two N-terminus residues. Angew. Chem. Int. Ed. Engl. 48(49), 9273-9276 (2009).
43. Drew SC, Masters CL, Barnham KJ. Alanine-2 carbonyl is an oxygen ligand in Cu2+ coordination of Alzheimer's disease amyloid-b peptide - relevance to N-terminally truncated forms. J. Am. Chem. Soc. 131(25), 8760-8761 (2009).
44. Zirah S, Kozin SA, Mazur AK et al. Structural changes of region 1-16 of the Alzheimer disease amyloid b-peptide upon zinc binding and in vitro aging. J. Biol. Chem. 281(4), 2151-2161 (2006).
45. Faller P, Hureau C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-b peptide. Dalton Trans. (7), 1080-1094 (2009).
46. Karr JW, Szalai VA. Role of aspartate-1 in Cu(II) binding to the amyloid-b peptide of Alzheimer's disease. J. Am. Chem. Soc. 129(13), 3796-3797 (2007).
47. Karr JW, Akintoye H, Kaupp LJ, Szalai VA. N-terminal deletions modify the Cu2+ binding site in amyloid-b. Biochemistry 44(14), 5478-5487 (2005).
48. Garzon-Rodriguez W, Yatsimirsky AK, Glabe CG. Binding of Zn(II), Cu(II), and Fe(II) ions to Alzheimer's Ab peptide studied by fluorescence. Bioorg. Med. Chem. Lett. 9(15), 2243-2248 (1999).
49. Huang X, Atwood CS, Moir RD et al. Zinc-induced Alzheimer's Ab1-40 aggregation is mediated by conformational factors. J. Biol. Chem. 272(42), 26464-26470 (1997).
50. Schlief ML, Craig AM, Gitlin JD. NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J. Neurosci. 25(1), 239-246 (2005).
51. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc. Natl Acad. Sci. USA 99(11), 7705-7710 (2002). nn Elegantly demonstrates that synaptic zinc is crucially involved in amyloid deposition within the cortex.
52. Terry RD. The pathogenesis of Alzheimer disease: An alternative to the amyloid hypothesis. J. Neuropathol. Exp. Neurol. 55(10), 1023-1025 (1996).
53. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J. A role for synaptic zinc in activity-dependent Ab oligomer formation and accumulation at excitatory synapses. J. Neurosci. 29(13), 4004-4015 (2009). n Further elucidates the role of synaptic zinc in AD, showing that vesicular zinc released during neurotransmission is critical for amyloid-b oligomer synaptic targeting.
54. Uranga RM, Giusto NM, Salvador GA. Effect of transition metals in synaptic damage induced by amyloid b peptide. Neuroscience 170(2), 381-389 (2010).
55. Rauk A. The chemistry of Alzheimer's disease. Chem. Soc. Rev. 38(9), 2698-2715 (2009).
56. Rozga M, Bal W. The Cu(II)/Ab/human serum albumin model of control mechanism for copper-related amyloid neurotoxicity. Chem. Res. Toxicol. 23(2), 298-308 (2009).
57. Suh YH, Checler F. Amyloid precursor protein, presenilins, and a-synuclein: Molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol. Rev. 54(3), 469-525 (2002).
58. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: Relevance to Alzheimer's disease. Int. J. Biochem. Cell Biol. 35(11), 1505-1535 (2003).
59. Gandy S. The role of cerebral amyloid b accumulation in common forms of Alzheimer disease. J. Clin. Invest. 115(5), 1121-1129 (2005).
60. Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol. Aspects Med. 29(5), 258-289 (2008).
61. Bode W, Gomis-Ruth FX, Stockler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. FEBS Lett. 331(1-2), 134-140 (1993).
62. Allinson TM, Parkin ET, Turner AJ, Hooper NM. ADAMs family members as amyloid precursor protein a-secretases. J. Neurosci. Res. 74(3), 342-352 (2003).
63. Asai M, Hattori C, Szabo B et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP a-secretase. Biochem. Biophys. Res. Commun. 301(1), 231-235 (2003).
64. Fahrenholz F, Gilbert S, Kojro E, Lammich S, Postina R. a-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure. Ann. NY Acad. Sci. 920, 215-222 (2000).
65. Tanabe C, Hotoda N, Sasagawa N, Sehara-Fujisawa A, Maruyama K, Ishiura S. ADAM19 is tightly associated with constitutive Alzheimer's disease APP a-secretase in A172 cells. Biochem. Biophys. Res. Commun. 352(1), 111-117 (2007).
66. Buxbaum JD, Liu KN, Luo Y et al. Evidence that tumor necrosis factor a converting enzyme is involved in regulated a-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273(43), 27765-27767 (1998).
67. Kuhn PH, Wang H, Dislich B et al. ADAM10 is the physiologically relevant, constitutive a-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29(17), 3020-3032 (2010).
68. Postina R, Schroeder A, Dewachter I et al. A disintegrin- metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113(10), 1456-1464 (2004).
69. Hartmann D, de Strooper B, Serneels L et al. The disintegrin/ metalloprotease ADAM 10 is essential for Notch signalling but not for a-secretase activity in fibroblasts. Hum. Mol. Genet. 11(21), 2615-2624 (2002).
70. Silvestri L, Camaschella C. A potential pathogenetic role of iron in Alzheimer's disease. J. Cell. Mol. Med. 12(5A), 1548-1550 (2008).
71. Borchardt T, Camakaris J, Cappai R, Masters CL, Beyreuther K, Multhaup G. Copper inhibits b-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion. Biochem. J. 344(Pt 2), 461-467 (1999).
72. Yan R, Bienkowski MJ, Shuck ME et al. Membrane-anchored aspartyl protease with Alzheimer's disease b-secretase activity. Nature 402(6761), 533-537 (1999).
73. Vassar R, Bennett BD, Babu-Khan S et al. b-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440), 735-741 (1999).
74. Sinha S, Anderson JP, Barbour R et al. Purification and cloning of amyloid precursor protein b-secretase from human brain. Nature 402(6761), 537-540 (1999).
75. Luo Y, Bolon B, Kahn S et al. Mice deficient in BACE1, the Alzheimer's b-secretase, have normal phenotype and abolished b-amyloid generation. Nat. Neurosci. 4(3), 231-232 (2001).
76. Cai H, Wang Y, McCarthy D et al. BACE1 is the major b-secretase for generation of Ab peptides by neurons. Nat. Neurosci. 4(3), 233-234 (2001).
77. Angeletti B, Waldron KJ, Freeman KB et al. BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. J. Biol. Chem. 280(18), 17930-17937 (2005).
78. Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer b-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160(1), 113-123 (2003).
79. Schneider A, Rajendran L, Honsho M et al. Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J. Neurosci. 28(11), 2874-2882 (2008).
80. Hung YH, Robb EL, Volitakis I et al. Paradoxical condensation of copper with elevated b-amyloid in lipid rafts under cellular copper deficiency conditions: Implications for Alzheimer disease. J. Biol. Chem. 284(33), 21899-21907 (2009).
81. De Strooper B. Aph-1, Pen-2, and nicastrin with presenilin generate an active g-secretase complex. Neuron 38(1), 9-12 (2003).
82. Park IH, Jung MW, Mori H, Mook-Jung I. Zinc enhances synthesis of presenilin 1 in mouse primary cortical culture. Biochem. Biophys. Res. Commun. 285(3), 680-688 (2001).
83. Hoke DE, Tan JL, Ilaya NT et al. In vitro g-secretase cleavage of the Alzheimer's amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc. FEBS J. 272(21), 5544-5557 (2005).
84. Greenough MA, Volitakis I, Li QX et al. Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. J. Biol. Chem. 286(11), 9776-9786 (2011).
85. Nadal RC, Rigby SE, Viles JH. Amyloid b-Cu2+ complexes in both monomeric and fibrillar forms do not generate H2O2 catalytically but quench hydroxyl radicals. Biochemistry 47(44), 11653-11664 (2008).
86. Baruch-Suchodolsky R, Fischer B. Ab40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry 48(20), 4354-4370 (2009).
87. Whitson JS, Selkoe DJ, Cotman CW. Amyloid b protein enhances the survival of hippocampal neurons in vitro. Science 243(4897), 1488-1490 (1989).
88. Opazo C, Huang X, Cherny RA et al. Metalloenzyme-like activity of Alzheimer's disease b-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J. Biol. Chem. 277(43), 40302-40308 (2002).
89. Huang X, Cuajungco MP, Atwood CS et al. Cu(II) potentiation of alzheimer Ab neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 274(52), 37111-37116 (1999).
90. Jiang D, Men L, Wang J et al. Redox reactions of copper complexes formed with different b-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance. Biochemistry 46(32), 9270-9282 (2007).
91. Yoshimoto N, Tasaki M, Shimanouchi T, Umakoshi H, Kuboi R. Oxidation of cholesterol catalyzed by amyloid b-peptide (Ab)-Cu complex on lipid membrane. J. Biosci. Bioeng. 100(4), 455-459 (2005).
92. Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D. Formation of hydrogen peroxide and hydroxyl radicals from A(b) and a-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic. Biol. Med. 32(11), 1076-1083 (2002).
93. Dikalov SI, Vitek MP, Mason RP. Cupric-amyloid b peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical. Free Radic. Biol. Med. 36(3), 340-347 (2004).
94. Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid b peptide. Biochim. Biophys. Acta 1768(8), 1976-1990 (2007).
95. Puglielli L, Friedlich AL, Setchell KD et al. Alzheimer disease b-amyloid activity mimics cholesterol oxidase. J. Clin. Invest. 115(9), 2556-2563 (2005).
96. Nelson TJ, Alkon DL. Oxidation of cholesterol by amyloid precursor protein and b-amyloid peptide. J. Biol. Chem. 280(8), 7377-7387 (2005).
97. Murray IV, Sindoni ME, Axelsen PH. Promotion of oxidative lipid membrane damage by amyloid b proteins. Biochemistry 44(37), 12606-12613 (2005).
98. Haeffner F, Smith DG, Barnham KJ, Bush AI. Model studies of cholesterol and ascorbate oxidation by copper complexes: Relevance to Alzheimer's disease b-amyloid metallochemistry. J. Inorg. Biochem. 99(12), 2403-2422 (2005).
99. Ali FE, Separovic F, Barrow CJ et al. Methionine regulates copper/hydrogen peroxide oxidation products of Ab. J. Pept. Sci. 11(6), 353-360 (2005).
100. Ciccotosto GD, Tew D, Curtain CC et al. Enhanced toxicity and cellular binding of a modified amyloid b peptide with a methionine to valine substitution. J. Biol. Chem. 279(41), 42528-42534 (2004).
101. Chen K, Kazachkov M, Yu PH. Effect of aldehydes derived from oxidative deamination and oxidative stress on b-amyloid aggregation; pathological implications to Alzheimer's disease. J. Neural Transm. 114(6), 835-839 (2007).
102. Barnham KJ, Haeffner F, Ciccotosto GD et al. Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease b-amyloid. FASEB J. 18(12), 1427-1429 (2004).
103. Nagano S, Huang X, Moir RD, Payton SM, Tanzi RE, Bush AI. Peroxidase activity of cyclooxygenase-2 (COX-2) cross-links b-amyloid (Ab) and generates Ab-COX-2 hetero-oligomers that are increased in Alzheimer's disease. J. Biol. Chem. 279(15), 14673-14678 (2004).
104. Smith DP, Smith DG, Curtain CC et al. Copper-mediated amyloid-b toxicity is associated with an intermolecular histidine bridge. J. Biol. Chem. 281(22), 15145-15154 (2006).
105. Murray IV, Liu L, Komatsu H et al. Membrane-mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid b proteins. J. Biol. Chem. 282(13), 9335-9345 (2007).
106. Markesbery WR, Lovell MA. Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment. Arch. Neurol. 64(7), 954-956 (2007).
107. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 17(8), 2653-2657 (1997).
108. Smith MA, Perry G, Richey PL et al. Oxidative damage in Alzheimer's. Nature 382(6587), 120-121 (1996).
109. Yoshiike Y, Tanemura K, Murayama O et al. New insights on how metals disrupt amyloid b-aggregation and their effects on amyloid-b cytotoxicity. J. Biol. Chem. 276(34), 32293-32299 (2001).
110. Atwood CS, Moir RD, Huang X et al. Dramatic aggregation of Alzheimer Ab by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 273(21), 12817-12826 (1998).
111. Cherny RA, Legg JT, McLean CA et al. Aqueous dissolution of Alzheimer's disease Ab amyloid deposits by biometal depletion. J. Biol. Chem. 274(33), 23223-23228 (1999).
112. Ha C, Ryu J, Park CB. Metal ions differentially influence the aggregation and deposition of Alzheimer's b-amyloid on a solid template. Biochemistry 46(20), 6118-6125 (2007).
113. Tougu V, Karafin A, Zovo K et al. Zn(II)-and Cu(II)-induced non-fibrillar aggregates of amyloid-b1-42 peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators. J. Neurochem. 110(6), 1784-1795 (2009).
114. Sarell CJ, Wilkinson SR, Viles JH. Substoichiometric levels of Cu2+ ions accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-b from Alzheimer disease. J. Biol. Chem. 285(53), 41533-41540 (2010).
115. Tsvetkov PO, Kulikova AA, Golovin AV et al. Minimal Zn2+ binding site of amyloid-b. Biophys. J. 99(10), L84-L86 (2010).
116. Miller Y, Ma B, Nussinov R. Zinc ions promote Alzheimer Ab aggregation via population shift of polymorphic states. Proc. Natl Acad. Sci. USA 107(21), 9490-9495 (2010).
117. Atwood CS, Perry G, Zeng H et al. Copper mediates dityrosine cross-linking of Alzheimer's amyloid-b. Biochemistry 43(2), 560-568 (2004).
118. Gaggelli E, Grzonka Z, Kozlowski H et al. Structural features of the Cu(II) complex with the rat Ab1-28 fragment. Chem. Comm. (Camb.) (3), 341-343 (2008).
119. Eury H, Bijani C, Faller P, Hureau C. Copper(II) coordination to amyloid b: Murine versus human peptide. Angew. Chem. Int. Ed. Engl. 50(4), 901-905 (2011).
120. Vaughan DW, Peters A. The structure of neuritic plaque in the cerebral cortex of aged rats. J. Neuropathol. Exp. Neurol. 40(4), 472-487 (1981).
121. McColl G, Roberts BR, Gunn AP et al. The caenorhabditis elegans Ab1-42 model of Alzheimer disease predominantly expresses Ab3-42. J. Biol. Chem. 284(34), 22697-22702 (2009).
122. Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 29(3), 407-410 (2005).
123. Maurer I, Zierz S, Moller HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging 21(3), 455-462 (2000).
124. Cottrell DA, Blakely EL, Johnson MA, Ince PG, Turnbull DM. Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57(2), 260-264 (2001).
125. Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer's disease platelets. Neurobiol. Aging 25(1), 105-110 (2004).
126. De Deyn PP, Hiramatsu M, Borggreve F et al. Superoxide dismutase activity in cerebrospinal fluid of patients with dementia and some other neurological disorders. Alzheimer Dis. Assoc. Disord. 12(1), 26-32 (1998).
127. Omar RA, Chyan YJ, Andorn AC, Poeggeler B, Robakis NK, Pappolla MA. Increased expression but reduced activity of antioxidant enzymes in Alzheimer's disease. J. Alzheimers Dis. 1(3), 139-145 (1999).
128. Kanemitsu H, Tomiyama T, Mori H. Human neprilysin is capable of degrading amyloid b peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci. Lett. 350(2), 113-116 (2003).
129. Carson JA, Turner AJ. b-amyloid catabolism: Roles for neprilysin (NEP) and other metallopeptidases? J. Neurochem. 81(1), 1-8 (2002).
130. Iwata N, Tsubuki S, Takaki Y et al. Metabolic regulation of brain Ab by neprilysin. Science 292(5521), 1550-1552 (2001).
131. Farris W, Mansourian S, Chang Y et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid b-protein, and the b-amyloid precursor protein intracellular domain in vivo. Proc. Natl Acad. Sci. USA 100(7), 4162-4167 (2003).
132. Leissring MA, Farris W, Chang AY et al. Enhanced proteolysis of b-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40(6), 1087-1093 (2003).
133. Gomis-Ruth FX. Structural aspects of the metzincin clan of metalloendopeptidases. Mol. Biotechnol. 24(2), 157-202 (2003).
134. Grasso G, Pietropaolo A, Spoto G et al. Copper(I) and copper(II) inhibit Ab peptides proteolysis by insulin-degrading enzyme differently: Implications for metallostasis alteration in Alzheimer's disease. Chemistry 17(9), 2752-2762 (2011).
135. Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM. Age-and region-dependent alterations in Ab-degrading enzymes: Implications for Ab-induced disorders. Neurobiol. Aging 26(5), 645-654 (2005).
136. Wang DS, Iwata N, Hama E, Saido TC, Dickson DW. Oxidized neprilysin in aging and Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 310(1), 236-241 (2003).
137. Shinall H, Song ES, Hersh LB. Susceptibility of amyloid b peptide degrading enzymes to oxidative damage: A potential Alzheimer's disease spiral. Biochemistry 44(46), 15345-15350 (2005).
138. Li W, Poteet E, Xie L, Liu R, Wen Y, Yang SH. Regulation of matrix metalloproteinase 2 by oligomeric amyloid b protein. Brain Res. 1387, 141-148 (2011).
139. Crouch PJ, Tew DJ, Du T et al. Restored degradation of the Alzheimer's amyloid-b peptide by targeting amyloid formation. J. Neurochem. 108(5), 1198-1207 (2009).
140. Bjorkdahl C, Sjogren MJ, Winblad B, Pei JJ. Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells. Neuroreport 16(6), 591-595 (2005).
141. An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B, Pei JJ. Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3b in SH-SY5Y neuroblastoma cells. J. Neurochem. 92(5), 1104-1115 (2005).
142. Ostrakhovitch EA, Lordnejad MR, Schliess F, Sies H, Klotz LO. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch. Biochem. Biophys. 397(2), 232-239 (2002).
143. White AR, Du T, Laughton KM et al. Degradation of the Alzheimer disease amyloid b-peptide by metal-dependent up-regulation of metalloprotease activity. J. Biol. Chem. 281(26), 17670-17680 (2006).
144. Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 21(2), 75-80 (1998).
145. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nat. Genet. 39(1), 17-23 (2007).
146. Robson KJ, Lehmann DJ, Wimhurst VL et al. Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. J. Med. Genet. 41(4), 261-265 (2004).
147. Malm TM, Iivonen H, Goldsteins G et al. Pyrrolidine dithiocarbamate activates Akt and improves spatial learning in APP/PS1 mice without affecting b-amyloid burden. J. Neurosci. 27(14), 3712-3721 (2007).
148. Paul CM, Magda G, Abel S. Spatial memory: Theoretical basis and comparative review on experimental methods in rodents. Behav. Brain Res. 203(2), 151-164 (2009).
149. Morris RGM. Spatial localization does not require the presence of local cues. Learning Motivation 12(2), 239-260 (1981).
150. Crouch PJ, Hung LW, Adlard PA et al. Increasing Cu bioavailability inhibits Ab oligomers and t phosphorylation. Proc. Natl Acad. Sci. USA 106(2), 381-386 (2009).
151. Stewart S, Cacucci F, Lever C. Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer's mouse model. J. Alzheimers Dis. DOI: 10.3233/JAD-2011-101827 (2011).
152. Linkous DH, Adlard PA, Wanschura PB, Conko KM, Flinn JM. The effects of enhanced zinc on spatial memory and plaque formation in transgenic mice. J. Alzheimers Dis. 18(3), 565-579 (2009).
153. Stoltenberg M, Bush AI, Bach G et al. Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency. Neuroscience 150(2), 357-369 (2007).
154. Railey AM, Groeber CM, Flinn JM. The effect of metals on spatial memory in a transgenic mouse model of Alzheimer's disease. J. Alzheimers Dis. 24(2), 375-381 (2011).
155. Sandstead HH. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Am. J. Clin. Nutr. 61(Suppl. 3), S621-S624 (1995).
156. Flinn JM, Hunter D, Linkous DH et al. Enhanced zinc consumption causes memory deficits and increased brain levels of zinc. Physiol. Behav. 83(5), 793-803 (2005).
157. Sinha S, Taly AB. Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: Promising, safe and cheap. J. Neurol. Sci. 264(1-2), 129-132 (2008).
158. Cherny RA, Atwood CS, Xilinas ME et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits b-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30(3), 665-676 (2001).
159. Grossi C, Francese S, Casini A et al. Clioquinol decreases amyloid-b burden and reduces working memory impairment in a transgenic mouse model of Alzheimer's disease. J. Alzheimers Dis. 17(2), 423-440 (2009).
160. Schafer S, Pajonk FG, Multhaup G, Bayer TA. Copper and clioquinol treatment in young APP transgenic and wild-type mice: Effects on life expectancy, body weight, and metal-ion levels. J. Mol. Med. 85(4), 405-413 (2007).
161. Adlard PA, Cherny RA, Finkelstein DI et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Ab. Neuron 59(1), 43-55 (2008). nn Highlights the potential efficacy of metal-targeted approaches in preventing the cognitive decline and progression of AD-like pathology in two transgenic mouse models of AD.
162. Adlard PA, Bica L, White AR et al. Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease. PLoS One 6(3), E17669 (2011).
163. Lee JY, Friedman JE, Angel I, Kozak A, Koh JY. The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human b-amyloid precursor protein transgenic mice. Neurobiol. Aging 25(10), 1315-1321 (2004).
164. Rezai-Zadeh K, Shytle D, Sun N et al. Green tea epigallocatechin-3- gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci. 25(38), 8807-8814 (2005).
165. Morel I, Lescoat G, Cogrel P et al. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem. Pharmacol. 45(1), 13-19 (1993).
166. Quesada IM, Bustos M, Blay M et al. Dietary catechins and procyanidins modulate zinc homeostasis in human HepG2 cells. J. Nutr. Biochem. 22(2), 153-163 (2010).
167. Weinreb O, Amit T, Mandel S, Youdim MB. Neuroprotective molecular mechanisms of (-)-epigallocatechin-3-gallate: A reflective outcome of its antioxidant, iron chelating and neuritogenic properties. Genes Nutr. (2009).
168. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J. Alzheimers Dis. 6(4), 367-377; discussion 443-449 (2004).
169. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci. 21(21), 8370-8377 (2001).
170. Yang F, Lim GP, Begum AN et al. Curcumin inhibits formation of amyloid b oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 280(7), 5892-5901 (2005).
171. Boldron C, Van der Auwera I, Deraeve C et al. Preparation of cyclo-phen-type ligands: Chelators of metal ions as potential therapeutic agents in the treatment of neurodegenerative diseases. Chembiochem 6(11), 1976-1980 (2005).
172. Dedeoglu A, Cormier K, Payton S et al. Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis. Exp. Gerontol. 39(11-12), 1641-1649 (2004).
173. Kessler H, Bayer TA, Bach D et al. Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: A pilot Phase 2 clinical trial. J. Neural Transm. 115(8), 1181-1187 (2008).
174. Kessler H, Pajonk FG, Bach D et al. Effect of copper intake on CSF parameters in patients with mild Alzheimer's disease: A pilot Phase 2 clinical trial. J. Neural Transm. 115(12), 1651-1659 (2008).
175. Squitti R, Rossini PM, Cassetta E et al. d-penicillamine reduces serum oxidative stress in Alzheimer's disease patients. Eur. J. Clin. Invest. 32(1), 51-59 (2002).
176. McLachlan DR, Smith WL, Kruck TP. Desferrioxamine and Alzheimer's disease: Video home behavior assessment of clinical course and measures of brain aluminum. Ther. Drug Monit. 15(6), 602-607 (1993).
177. Baum L, Lam CW, Cheung SK et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J. Clin. Psychopharmacol. 28(1), 110-113 (2008).
178. Ritchie CW, Bush AI, Mackinnon A et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Ab amyloid deposition and toxicity in Alzheimer disease: A pilot Phase 2 clinical trial. Arch. Neurol. 60(12), 1685-1691 (2003).
179. Lannfelt L, Blennow K, Zetterberg H et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Ab as a modifying therapy for Alzheimer's disease: A Phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 7(9), 779-786 (2008). nn Further highlights the potential efficacy of the metal-targeted approach for the treatment of AD, describing a positive clinical outcome in a short-term human trial.
180. Faux NG, Ritchie CW, Gunn A et al. PBT2 rapidly improves cognition in Alzheimer's disease: Additional Phase II analyses. J. Alzheimers Dis. 20(2), 509-516 (2010). Patent
181. Kozak A, Shapiro I. WO/1999/016741 (1999). Websites