Computational insights into the development of novel therapeutic strategies for Alzheimers disease

Future Medicinal Chemistry

Volumn 1, Issue 1, 2009, Pages 119-135

  Prabhakar, Rajeev ^a  

^a Department of Biology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; METAL ION;

ALZHEIMER DISEASE; AMYLOIDOSIS; BIOINFORMATICS; CHEMICAL ANALYSIS; HUMAN; MOLECULAR DYNAMICS; NONHUMAN; OLIGOMERIZATION; OXIDATIVE STRESS; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN HYDROLYSIS; PROTEIN SYNTHESIS; QUANTUM MECHANICS; REVIEW; SEQUENCE ANALYSIS; SPECTROSCOPY;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; COMPUTATIONAL BIOLOGY; HUMANS; METALS; MOLECULAR DYNAMICS SIMULATION; PROTEASE INHIBITORS;

EID: 77951887347     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.09.10     Document Type: Review

References (235)

1. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 430, 631-639 (2004).
2. Iversen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS. The toxicity in vitro of b-amyloid protein. Biochem. J. 311, 1-16 (1995).
3. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356 (2002).
4. Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ. b-amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms J. Biol. Chem. 268, 3021-3024 (1993).
5. Weidemann A, Eggert S, Reinhard F et al. A novel ε-cleavage within the transmembrane domain of the alzheimer amyloid precursor protein demonstrates homology with notch processing. Biochemistry 41, 2825-2835 (2002).
6. Haass C, Schlossmacher M, Hung AY et al. Amyloid b-peptide is produced by cultured cells during normal metabolism. Nature 359, 322-325 (1992).
7. Seubert P, Vigo-Pelfrey C, Esch F et al. Isolation and quantitation of soluble Alzheimer's b-peptide from biological fluids. Nature 359, 325-327 (1992).
8. Shoji M, Golde TE, Ghiso J et al. Production of the Alzheimer amyloid b protein by normal proteolytic processing. Science 258, 126-129 (1992).
9. 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, 735-741 (1999).
10. Yan R, Bienkowski ME, Shuck ME et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533-537 (1999).
11. Sinha S, Anderson JP, Barbour R et al. Purification and cloning of amyloid precursor protein -secretase from human brain. Nature 402, 537-540 (1999).
12. Strooper BD, Saftig P, Craessaerts K et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387-390 (1998).
13. Debomoy K, Lahiri N. Lethal weapon: amyloid b-peptide, the role in the oxidative stress and neurodegeneration of Alhzeimer's disease. Neurobiol. Aging 25, 581-587 (2004).
14. Simmons LK, May PC, Tomaselli K et al. Secondary structure of amyloid b peptide correlates with neurotoxic activity in vitro. Mol. Pharmacol. 45, 373-379 (1994).
15. Pike CJ, Walencewicz-Wasserman JA, Kosmoski J et al. Structure-activity analysis of b-amyloid peptides: contributions of the b(25-35) region to aggregation and neurotoxicity. J. Neurochem. 64, 253-265 (1995).
16. Oda T, Wals P, Osterburg HH et al. Clusterin (apoJ) Alters the aggregation of amyloid b-peptide (ab1-42) and forms slowly sedimenting ab complexes that cause oxidative stress. Exp. Neurol. 136, 22-31 (1995).
17. Wujek JR, Dority MD, Frederickson RC, Brunden KR. Deposits of Ab fibrils are not toxic to cortical and hippocampal neurons in vitro. Neurobiol. Aging 17, 107-113 (1996).
18. Huang X, Atwood CS, Hartshorn MA et al. The Ab peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38, 7609-7616 (1999).
19. Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF. Oxidative damage in Alzhemier's disease. Nature 382, 120-121 (1996).
20. Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer's amyloid b-peptide-association free radical oxidative stress and neurotoxicity. J. Struct. Biol. 130, 184-208 (2000).
21. Lovell M, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158, 47-52 (1998).
22. Leissring MA. The ABCs of Ab-cleaving proteases. J. Biol. Chem. 283, 29645-29649 (2008).
23. Tjernberg LO, Näslund J, Lindqvist F et al. Arrest of b-amyloid fibril formation by a pentapeptide ligand. J. Biol. Chem. 271, 8545-8548 (1996).
24. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49-60 (2003).
25. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B. b-sheet breaker peptides inhibit fibrillogenesis is a rat brain model of amyloidosis: implications for Alzheimer's therapy. Nat. Med. 4, 822-826 (1998).
26. Schenk DB, Rydel RE, May P et al. Therapeutic approaches related to amyloid-b peptide and Alzheimer's disease. J. Med. Chem. 38, 4141-4154 (1995).
27. Ghanta J, Shen CL, Kiessling LL, Murphy RM. A strategy for designing inhibitors of b-amyloid toxicity. J. Biol. Chem. 271, 29525-29528 (1996).
28. Soto C, Kindy MS, Baumann M, Frangione B. Inhibition of of Alzheimer's amyloidosis by peptides that prevent b-sheet conformation. Biochem. Biophys. Res. Commun. 226, 672-680 (1996).
29. Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG, Szarek WA. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat. Med. 1, 143-148 (1995).
30. Lorenzo A, Yankner BA. b-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl Acad. Sci. USA 91, 12243-12247 (1994).
31. Nakagami Y, Nishimura S, Murasugi T et al. A novel-sheet breaker, RS-0406, reverses amyloid-induced cytotoxicity and impairment of long-term potentiation in vitro. Brit. J. Pharmacol. 137, 676-682 (2002).
32. Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E, Perfetti V. Interaction of the anthracycline 4́-iodo-4́-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc. Natl Acad. Sci. USA 92, 2959-2963 (1995).
33. Wood SJ, Mackenzie L, Maleeff B, Hurle MR, Wetzel R. Selective Inhibition of Ab FIBRIL formation. J. Biol. Chem. 271, 4086-4092 (1996).
34. Howlett D, Cutler P, Heales S, Camilleri P. Hemin and related porphyrins inhibit b-amyloid aggregation. FEBS Letts. 417, 249-251 (1997).
35. Pappolla M, Bozner P, Soto C et al. Inhibition of Alzheimer b-fibrillogenesis by melatonin. J. Biol. Chem. 273, 7185-7188 (1998).
36. Cherny RA, Legg JT, McLean CA. Aqueous dissolution of Alzheimer's disease Ab amyloid deposits by biometal depletion. J. Biol. Chem. 274, 23223-23228 (1999).
37. Lashuel HA, Hartley DM, Balakhaneh D. New class of inhibitors of amyloid-b fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease. J. Biol. Chem. 277, 42881-42890 (2002).
38. Ray I, Chauhan A, Wegiel J, Chauhan VPS. Gelsolin inhibits the fibrillization of amyloid b-protein, and also defibrillizes its preformed fibrils. Brain Res. 853, 344-351 (2000).
39. Kim HJ, Chae SC, Lee DK et al. Selective neuronal degeneration induced by soluble oligomeric amyloid b protein. FASEB J. 17, 118-120 (2003).
40. Permanne B, Adessi C, Saborio GP et al. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a b-sheet breaker peptide. FASEB J. 16, 165-188 (2002).
41. Triguero L, Singh R, Prabhakar R. Comparative molecular dynamics studies of wild-type and oxidized forms of full length Alzheimer's amyloid peptide b-peptides Ab(1-40) and Ab(1-42). J. Phys. Chem. B 112, 7123-7131 (2008).
42. Yu N, Hayik SA, Wang B, Liao N, Reynolds CH, Merz KM. Assigning the protonation states of the key aspartates in g-secretase using QM/MM x-ray structure refinement. J. Chem. Theory Comput. 2, 1057-1069 (2006).
43. Singh R, Barman A, Prabhakar R. computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid b-peptides (Ab40 and Ab42). J. Phys. Chem. B 113(10), 2990-2999 (2009).
44. Baumketner A, Shea JE. The structure of the alzeimer amyloid b 10-35 peptide probed through replica exchange molecular dynamics simulations in explicit solvent. J. Mol. Biol. 366, 275-285 (2007).
45. Massi F, Peng JW, Lee PJ, Straub JE. Simulation study of the structure and dynamics of the Alhzeimer's amyloid peptide congener in solution. Biophys. J. 80, 31-44 (2001).
46. Triguero L, Singh R, Prabhakar RA. Molecular dynamics study to investigate the effect of chemical substitutions of methionine35 on the secondary structure of the amyloid B (Ab(1-42)) monomer in aqueous solution. J. Phys. Chem. B 112, 2159-2167 (2008).
47. Barman A, Taves W Prabhakar R. Insights into the mechanism of methionine oxidation catalyzed by metal (Cu2+, Zn2+ and Fe3+) - amyloid B (Ab) peptide complexes. A computational study. J. Comput. Chem. DOI: 10.1002/jcc.21167 (2008) (Epub ahead of print).
48. Gnanakaran S, Nussinov R, García AE. Atomic-level description of amyloid b-dimer formation. J. Am Chem Soc. 128, 2158-2159 (2006).
49. Urbanc B, Cruz L, Ding L. Molecular dynamics simulation of amyloid b dimer formation. Biophys. J. 87, 2310-2321 (2004).
50. Hwang W, Zhang S, Kamm RD, Karplus M. Kinetic control of dimer structure formation in amyloid fibrillogenesis Proc. Natl Acad. Sci. USA 101, 12916-12921 (2004).
51. Buchete NV, Tycko R, Hummer G. Molecular dynamics simulations of Alzheimer's b-amyloid protofilaments. J. Mol. Biol. 353, 804-821 (2005).
52. Lazo ND, Maji SK, Fradinger EA, Bitan G, Teplow DB. The amyloid b protein. In: Amyloid Proteins. The b Sheet Conformation and Disease. Sipe JD (Ed.). Wiley-VCH Verlag GmbH & Co., Weinheim, Germany, 385-491 (2005).
53. Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619 (2008).
54. Whitson JS, Selkoe DJ, Cotman CW. Amyloid b protein enhances the survival of hippocampal neurons in vitro. Science 243, 1488-1490 (1989).
55. Yankner BA, Duffy LK. Kirschner DA. Neurotrophic and neurotoxic effects of amyloid b protein: reversal by tachykinin neuropeptides. Science 250, 279-282 (1990).
56. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. In vitro aging of b-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563, 311-314 (1991).
57. Busciglio J, Lorenzo A, Yankner B. Methological variables in the assessment of b-amyloid neurotoxicity. Neurobiol. Aging 13, 609-612 (1992).
58. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA. Aging renders the brain vulnerable to amyloid b-protein neurotoxicity. Nat. Med. 827-831 (1998).
59. Selkoe DJ. Alzheimer's disease - genotypes, phenotype, and treatments. Science 275, 630-631 (1997).
60. Hardy J. Amyloid, the presenilins and Alzheimer disease. Trends Neurosci. 20, 154-159 (1997).
61. Lamb BT. Presenilins, amyloid-bold b and Alzheimer's disease. Nature Med. 3, 28-29 (1997).
62. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina H, Ihara Y. Visualization of Ab42(43) and Ab40 in senile plaques with end-specific Ab monoclonals: evidence that an initially deposited species is Ab42(43). Neuron 13, 45-53 (1994).
63. Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl Acad. Sci. USA 99, 775-779 (2002).
64. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of g-secretase activity. Nat. Cell Biol. 5, 486-488 (2003).
65. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. g-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl Acad. Sci. USA 100, 6382-6387 (2003).
66. Takasugi N, Tomita T, Hayashi I et al. The role of presenilin cofactors in the g-secretase complex. Nature 422, 438-441 (2003).
67. Kim SH, Ikeuchi T, Yu C, Sisodia SS. Regulated hyperaccumulation of presenilin-1 and the 'g-secretase' complex. Evidence for differential intramembranous processing of transmembrane subatrates. J. Biol. Chem. 278, 33992-34002 (2003).
68. Wolfe MS, Xia W, Moore CL et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer's g-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38, 4720-4727 (1999).
69. Shearman MS, Beher D, Clarke EE et al. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid b-protein precursor g-secretase activity. Biochemistry 39, 8698-8704 (2000).
70. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and g-secretase activity. Nature 398, 513-517 (1999).
71. Cacquevel M, Aeschbach L, Osenkowski P. Rapid purification of active g-secretase, an intramembrane protease implicated in Alzheimer's disease. J. Neurochem. 104, 210-220 (2008).
72. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. Electron microscopic structure of purified, active g-secretase reveals an aqueous intramembrane chamber and two pores. Pro. Natl Acad. Sci. USA 103, 6889-6894 (2006).
73. Spasic D, Annaert W. Building g-secretase - the bits and pieces. J. Cell Sci. 121, 413-420 (2007).
74. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Complex N-linked glycosylated nicastrin associates with active g-secretase and undergoes tight cellular regulation. J. Biol. Chem. 277, 35113-35117 (2002).
75. Steiner H, Duff K, Capell A et al. A loss of function mutation of presenilin-2 interferes with amyloid b-peptide production and notch signaling. J. Biol. Chem. 274, 28669-28673 (1999).
76. Xia X, Qian S, Soriano S et al. Loss of presenilin 1 is associated with enhanced b-catenin signaling and skin tumorigenesis. Pro. Natl Acad. Sci. USA 98, 10863-10868 (2001).
77. Suzuki N, Cheung TT, Cai XD et al. An increased percentage of long amyloid b protein secreted by familial amyloid b protein precursor (b APP717) mutants. Science 264, 1336-1340 (1994).
78. Patel S, Vuillard L, Cleasby A, Murray CW, Yon J. Apo and inhibitor complex structures of BACE (b-secretase). J. Mol. Biol. 343, 407-416 (2004).
79. Hong L, Koelsch G, Lin X et al. Structure of the protease domain of memapsin 2 (b-secretase) complexed with inhibitor. Science 290, 150-153 (2000).
80. Hong L, Turner RT III, Koelsch G et al. Crystal structure of memapsin 2 (b-secretase) complexed with an inhibitor OM00-3. Biochemistry 41, 10963-10967 (2002).
81. Cascella M, Micheletti C, Rothlisberger U, Carloni P. Evolutionarily conserved functional mechanics across pepsin-like and retroviral aspartic proteases. J. Am. Chem. Soc. 127, 3734-3742 (2005).
82. Chatfield D, Eurenius CP, Brooks K, Bernard R. HIV-1 protease cleavage mechanism: a theoretical investigation based on classical MD simulation and reaction path calculations using a hybrid QM/MM potential. J. Mol. Struct. Theochem. 423, 79-92 (1998).
83. Piana S, Bucher D, Carloni P, Rothlisberger U. Reaction mechanism of HIV-1 protease by hybrid Car-parrinello/classical MD simulations. J. Phys. Chem. B 108, 11139-11149 (2004).
84. Trylska J, Grochowski P, McCammon JA. The role of hydrogen bonding in the enzymatic reaction catalyzed by HIV-1 protease. Protein Sci. 13, 513-528 (2004).
85. Bjelic S, Åqvist J. Catalysis and linear free energy relationship in aspartic proteases. Biochemistry 45, 7709-7723 (2006).
86. Bjelic S, Åqvist J. computational prediction of structure, substrate binding mode, mechanism, and rate for a malaria protease with a novel type of active site. Biochemistry 43, 14521-14528 (2004).
87. Pearl L, Blundell T. The active site of aspartic proteinases. FEBS Lett. 174, 96-101 (1984).
88. Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR. Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: Implications for a mechanism of action. Proc. Natl Acad. Sci. USA 84, 7009-7013 (1987).
89. Rodriguez EJ, Angeles TS, Meek TD. Use of nitrogen-15 kinetic isotope effects to elucidate details of the chemical mechanism of human imunodeficiency virus-1 proteases. Biochemistry 12380-12385 (1993).
90. Meek TD, Rodriguez EJ, Angeles TS. Use of steady-state kinetic methods to elucidate the kinetic and chemical mechanisms of retroviral proteases. Meth. Enzymol. 241, 127-156 (1994).
91. Brown RS, Bennet AJ, Slebocka-Tilk H. Recent perspectives concerning the mechanism of H3O+- and hydroxidepromoted amide hydrolysis. Acc. Chem. Res. 25, 481-488 (1992).
92. Coates L, Tuan H-F, Tomanicek S et al. The catalytic mechanism of an aspartic proteinase explored with neutron and x-ray diffraction. J. Am. Chem. Soc. 130, 7235-7237 (2008).
93. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 284, 770-776 (1999).
94. Weggen S, Eriksen JL, Das P et al. A subset of NSAIDs lower amyloidogenic A42 independently of cyclooxygenase activity. Nature 414, 212-216 (2001).
95. Cole SL, Vassar R. The Alzheimer's disease b-secretase enzyme, BACE1. Mol. Neurodegener. 2, 22 (2007).
96. Willem M, Garratt AN, Novak B et al. Control of peripheral nerve myelination by the b-secretase BACE1. Science 314, 664-666 (2006).
97. Wong HK, Sakurai T, Oyama F et al. b subunits of voltage-gated sodium channels are novel substrates of b-site amyloid precursor protein-cleaving enzyme (BACE1) and g-secretase. J. Biol. Chem. 280, 23009-23017 (2005).
98. Laird FM, Cai H, Savonenko AV et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-b amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693-11709 (2005).
99. Dominguez D, Tournoy J, Hartmann D et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem. 280, 30797-30806 (2005).
100. Harrison SM, Harper AJ, Hawkins J et al. BACE1 (b-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol. Cell. Neurosci. 24, 646-655 (2003).
101. Roberds SL, Anderson J, Basi G et al. BACE knockout mice are healthy despite lacking the primary b-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Gen. 10, 1317-1324 (2001).
102. Cole SL, Vassar R. The role of amyloid precursor protein processing by BACE1, the b-secretase, in Alzheimer's disease pathophysiology. J. Biol. Chem. 283, 29621-29625 (2008).
103. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL. BACE1 is the major b-secretase for generation of Ab peptides by neurons. Nat. Neurosci. 4, 233-234 (2001).
104. 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, 231-232 (2001).
105. Hong L, Koelsch G, Lin X et al. structure of the protease domain of memapsin 2 (b-secretase) complexed with inhibitor. Science 290, 150-153 (2000).
106. Hersh LB. The insulysin (insulin degrading enzyme) enigma. Cell. Mol. Life Sci. 63, 2432-2434 (2006).
107. Turner AJ, Nalivaeva NN. New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. Int. Rev. Neurobiol. 82, 113-135 (2007).
108. Wang DS, Dickson DW, Malter JS. b-amyloid degradation and Alzheimer's disease. J. Biomed. Biotechnol. 2006, 58406-58418 (2006).
109. Iwata N, Tsubuki S, Takaki Y et al. Identification of the major Ab1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 6, 143-150 (2000).
110. Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Ab peptide: the many roads to perdition. Neuron 43, 605-608 (2004).
111. Turner AJ, Nalivaeva NN. Proteinase dysbalance in pathology: the neprilysins (NEP) and antgiotensin-converting enzyme (ACE) families. Cell. Mol. Biol. 52, 40-48 (2006).
112. Yin KJ, Cirrito JR, Yan P et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-b peptide catabolism. J. Neurosci. 26, 10939-10948 (2006).
113. 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, 113-116 (2003).
114. Tucker HM, Kihiko M, Caldwell JN et al. The plasmin system is induced by and degrades amyloid-b aggregates J. Neurosci. 20, 3937-3946 (2000).
115. Mueller-Steiner S, Zhou Y, Arai H et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703-714 (2006).
116. Eckman EA, Reed DK. Eckman CB. Degradation of the Alzheimer's amyloid b peptide by endothelin-converting enzyme. J. Biol. Chem. 276, 24540-24548 (2001).
117. Eckman EA, Watson M, Marlow L, Sambamurti K, Eckman CB. Alzheimer's disease b-amyloid peptide is increased in mice deficient in endothelin- converting enzyme. J. Biol. Chem. 278, 2081-2084 (2003).
118. Eckman EA, Adams SK, Troendle FJ et al. Regulation of steady-state b-amyloid levels in the brain by neprilysin and endothelinconverting enzyme but not angiotensinconverting enzyme. J. Biol. Chem. 281, 30471-30478 (2006).
119. Iwata N, Tsubuki S, Takaki Y et al. Metabolic regulation of brain Ab by neprilysin. Science 292, 1550-1552 (2001).
120. Miller BC, Eckman EA, Sambamurti K et al. Amyloid-b peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc. Natl Acad. Sci. USA 100, 6221-6226 (2003).
121. 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, 1087-1093 (2003).
122. Qiu WQ, Folstein MF. Insulin, insulindegrading enzyme and amyloid-b peptide in Alzheimer's disease: review and hypothesis. Neurobiol. Aging 27, 190-198 (2006).
123. Taubes G. Neuroscience. Insulin insults may spur Alzheimer's disease. Science 301, 40-41 (2003).
124. Jacobsen JS, Comery TA, Martone RL et al. Enhanced clearance of A in brain by sustaining the plasmin proteolysis cascade. Proc. Natl Acad. Sci. 105, 8754-8759 (2008).
125. Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545-555 (2005).
126. Findeis MA. Approaches to discovery and characterization of inhibitors of amyloid b-peptide polymerization. Biochim. Biophys. Acta 1502, 76-84 (2000).
127. Levy E, Carman MD, Fernandez-Madrid IJ et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch-type. Science 248, 1124-1126 (1990).
128. Walsh DM, Lomakin A, Benedek GB, Maggio JE, Condron MM, Teplow DB. Amyloid b-protein fibrillogenesis: detection of a protofibrillar intermediate. J. Biol. Chem. 272, 22364-223742 (1997).
129. Corder EH, Saunders AM, Strittmatter WJ. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923 (1993).
130. Rovelet-Lecrux A, Hannequin D, Raux G. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24-26 (2006).
131. Bentahir M, Nyabi O, Verhamme J et al. Presenilin clinical mutations can affect g-secretase activity by different mechanisms. J. Neurochem. 96, 732-742 (2006).
132. Hsia AY, Masliah E, McConlogue L et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228-3233 (1998).
133. Lambert MP, Barlow AK, Chromy BA et al. Diffusible nonfibrillar ligands derived from Ab1-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448-6453 (1998).
134. Goldsbury CS, Wirtz S, Muller SA et al. Studies on the in vitro assembly of Ab1-40: implications for the search for a b fibril formation inhibitors. J. Struct. Biol. 130, 217-231 (2000).
135. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Kraft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid-peptides differentially affect neuronal viability. J. Biol. Chem. 277, 32046-32053 (2002).
136. Deshpande A, Mina E, Glabe C, Busciglio J. Different conformations of amyloid b induce neurotoxicity by distinct mechanisms in human cortical neurons. J. Neurosci. 26, 6011-6018 (2006).
137. McLean CA, Cherny RA, Fraser F et al. Soluble pool of Ab amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860-866 (1999).
138. Wang J, Dickson DW, Trojanowski JQ, Lee VM. The levels of soluble versus insoluble brain Ab distinguish Alzheimer's disease from normal and pathologic aging. Exp. Neurol 158, 328-337 (1999).
139. Kuo WL, Gehm BD, Rosner MR. Cloning and expression of the cDNA for a Drosophila insulin-degrading enzyme. Mol. Endocrinol. 4, 1580-1591 (1990).
140. Vigo-Pelfrey C, Lee D, Keim PS, Lieberburg I, Schenk D. Characterization of b-amyloid peptide from human cerebrospinal fluid. J. Neurochem. 61, 1965-1968 (1993).
141. Roher AE, Chaney MO, Kuo YM. Morphology and toxicity of Ab(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer's disease. J. Biol. Chem. 271, 20631-20635 (1996).
142. Enya M, Morishima-Kawashima M, Yoshimura M. Appearance of sodium dodecyl sulfate-stable amyloid b-protein (Ab) dimer in the cortex during aging. Am. J. Pathol. 154, 271-279 (1999).
143. Funato H, Enya M, Yoshimura M, Morishima-Kawashima M, Ihara Y. Presence of sodium dodecyl sulfate-stable amyloid b-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation. Am. J. Pathol. 155, 23-28 (1999).
144. Riek R, Guntert P, Dobeli H, Wuthrich K. NMR studies in aqueous solution fail to identify significant conformational differences between the monomeric forms of two Alhzeimer peptides with widely different plaque-competence, Ab(1-40)ox and Ab(1-42)ox. Eur. J. Biochem. 268, 5930-5936 (2001).
145. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedeck GB, Teplow DB. Amyloid b-protein (Ab) assembly: Ab40 and Ab42 oligomerize through distinct pathways. Proc. Natl Acad. Sci. USA 100, 330-335 (2003).
146. Bitan G, Teplow GB. Rapid photochemical cross-linking - a new tool for studies of metastable, amyloidogenic protein assemblies. Acc. Chem. Res. 37, 357-364 (2004).
147. Bitan G, Tarus B, Vollers SS et al. A molecular switch in amyloid assembly: met35 and amyloid b-protein oligomerization. J. Am. Chem. Soc. 125, 15359-15365 (2003).
148. Malinchick SB, Inouye H, Szumowski KE, Kirschner DA. Strcutural analysis of Alzheimer's b(1-40) amyloid: protofilament assembly of tubular fibrils. Biophys. J. 74, 537-545 (1998).
149. Tjernberg LO, Callaway DJE, Tjernberg A et al. A molecular model of alzheimer amyloid b-peptide fibril formation. J. Biol. Chem. 274, 12619-12625 (1999).
150. Tjernberg LO, Tjernberg A, Bark N et al. Assembling amyloid fibrils from designed structures containing a significant amyloid b-peptide fragment. Biochem. J. 366, 343-351 (2002).
151. Serpell LC, Blake CC, Fraser PE. Molecular structure of a fibrillar Alzheimer's Ab fragment. Biochemistry 39, 13269-13275 (2000).
152. Torok M, Milton S, Kayed R et al. Structural and dynamic features of Alzheimer's Ab peptide in amyloid fibrils studies by sitedirected spin labeling. J. Biol. Chem. 277, 40810-40815 (2002).
153. Antzutkin ON, Leapman RD, Balbach JJ, Tycko R. Supramolecular structural constraints on Alzheimer's b-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41, 15436-15450 (2002).
154. Antzutkin ON, Balbach JJ, Tycko R. Site-specific identification of non-b-strand conformations in Alzheimer's b-amyloid fibrils by solid-state NMR. Biophys. J. 84, 3326-3335 (2003).
155. Balbach JJ, Petkova AT, Oyler NA et al. Supramolecular structure in full-length Alzheimer's b-amyloid fibrils: evidence for a parallel b-sheet organization from solid-state nuclear magnetic resonance. Biophys. J. 83, 1205-1216 (2002).
156. Petkova AT, Ishii Y, Balbach JJ et al. A structural model for Alzheimer's b-amyloid fibrils based on experimental constrains from solid state NMR. Proc. Natl Acad. Sci. USA 99, 16742-16747 (2002).
157. Thompson LK. Unraveling the secrets of Alzheimer's b-amyloid fibrils. Proc. Natl Acad. Sci. USA 100, 383-385 (2003).
158. Petkova AT, Yaw WM, Tycko R. Experimental constraints on quaternary structure in Alzheimer's b-amyloid fibrils. Biochemistry 45, 498-512 (2006).
159. Paravastu AK, Petkova AT, Tycko R. Polymorphic fibril formation by residues 10-40 of the Alzheimer's b-amyloid peptide. Biophys. J. 90, 4618-4629 (2006).
160. Petkova AT, Leapman RD, Guo ZH, Yau WM, Mattson MP, Tycko R. Self-propagating molecular-level polymorphism in Alzheimer's b-amyloid fibrils. Science 307, 262-265 (2005).
161. Esler WP, Stimson ER, Ghilargi JR et al. Point substitution in the central hydrophobic cluster of a human b-amyloid congener disrupts peptide folding and abolishes plaque competence. Biochem. J. 35, 13914-13921 (1996).
162. Grabowski TJ, Cho HS, Vonsattel JPG, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann. Neurol. 49, 697-705 (2001).
163. Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB. In vitro studies of amyloid b-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-Gly) Alzheimer's disease. Biochem. J. 355, 869-877 (2001).
164. Nilsberth C, Westlind-Danielsson A, Eckman CB et al. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Ab protofibril formation. Nat. Neurosci. 4, 887-893 (2001).
165. Hou L, Shao H, Zhang Y et al. Solution NMR studies of the Ab(1-40) and Ab(1-42) peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation. J. Am. Chem. Soc. 126, 1992-2005 (2004).
166. Zhang S, Iwata K, Lachenmann MJ et al. The Alzheimer's peptide Ab adopts a collapsed coil sructure in water. J. Struct. Biol. 130, 130-141 (2000).
167. Lührs T, Titter C, Adrian M et al. 3D structure of Alzhemier's amyloid-b (1-42) fibrils. Proc. Natl Acad. Sci. USA 102, 17342-17347 (2005).
168. Dong J, Canfield JM, Mehta AK et al. Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity Proc. Natl Acad. Sci. USA 104, 13313-13318 (2007).
169. Burkoth TS, Benzinger TLS, Urban V et al. Structure of the b-amyloid fibril. J. Am. Chem. Soc. 122, 7883-7889 (2000).
170. Kohno T, Kobayashi K, Maeda T, Sato K, Takashima A. Three-dimensional structures of the amyloid-b peptide (25-35) in membranemimicking environment. Biochemistry 35, 16094-16104 (1996).
171. Antzutkin ON, Balbach JJ, Leapman RD, Nancy WR, Reed J, Tycko R. Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of b-sheets in Alzheimer's b-amyloid fibrils. Proc. Natl Acad. Sci. USA 97 13045-13050 (2000).
172. Wei G, Shea J-E. Effects of solvent on the structure of the Alzheimer Amyloid-b(25-35) Peptide. Biophys. J. 91, 1638-1647 (2006).
173. Baumketner A, Shea J-E. Folding landscapes of the Alzheimer amyloid-b(12-28) peptide. J. Mol. Biol. 362, 567-579 (2006).
174. Luttmann E, Fels G. All-atom moelcular dynamics studies of the full-length b-amyloid peptides. Chem. Phys. 323, 138-147 (2006).
175. Xu Y, Shen J, Luo X et al. Conformational transition of amyloid b-peptide. Proc. Natl Acad. Sci. USA 102, 5403-5407 (2004).
176. Itoh SG, Okamoto Y. Amyloid-b(29-42) dimer formation studied by multicanonical- mulytioverlap molecular dynamics simulations. J. Phys. Chem. B 112, 2767-2770 (2008).
177. Anand P, Nandel FS, Hansmann HE. The Alzheimer (Ab1-39) dimer in implicit solution. J. Chem. Phys. 129, 195102-195109 (2008).
178. Buchete NV, Hummer G. Structure and dynamics of parallel b-sheets, hydrophobic core, and loops in Alzheimer's Ab-fibrils. Biophys. J. 92, 3032-3039 (2007).
179. Lakdawala AS, Morgan DM, Liotta DC, Lynn DG, Snyder JP. Dynamics and fluidity of amyloid fibrils: a model of fibrous protein aggregates. J. Am. Chem. Soc. 124, 15150-15151 (2002).
180. Zhao Z, Singh R, Barman A, Johnson NF, Prabhakar R. Modeling the self-assembly dynamics of macromolecular protein aggregates underlying neurodegenerative disorders. Comput. Theor. Nanosci. (In press) (2008).
181. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neuro. Sci. 158, 47-52 (1998).
182. Dong J, Atwood CS, Anderson VE et al. Metal binding and oxidation of amyloid-b within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 42, 2768-2773 (2003).
183. Watson AA, Fairlie DP, Craik DJ. Solution structure of methionine-oxidized amyloid b-peptide (1-40). Does oxidation affect conformationa switching? Biochemistry 37, 12700-12706 (1998).
184. Brunelle P, Schoneich C, Rauk A. Oneelectron oxidation of methionine peptides stability of the three-electron S-N(amide) bond. Can. J. Chem. 84, 893-904 (2006).
185. Johansson AS, Bergquist J, Volbracht C et al. Attenuated amyloid-b aggregation and neurotoxicity to methionine oxidation. NeuroReport 18, 559-563 (2007).
186. Varadarajan S, Kanski J, Aksenova M, Lauderback C, Buetterfield DA. Different mechanism of oxidative stress and neurotoxicity for Alzheimer's Ab(1-42) and Ab(25-35). J. Am. Chem. Soc. 123, 5625-5631 (2001).
187. Stadman ER, Moskovitz J, Berlett BS, Levine RL. Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Mol. Cell. Biochem. 234, 3-9 (2002).
188. Kanski J, Varadarajan S, Aksenova M, Butterfield DA. Role of glycine-33, and methionine-35 in Alzheimer's amyloid b-peptide 1-42 associated oxidative stress and neurotoxicity. Biochem. Biophys. Acta 1586, 190-198 (2002).
189. Hou L, Kang I, Marchant RE, Zagorski MG. Methionine 35 oxidation reduces fibril assembly of the amyloid Ab-(1-42) peptide of Alzheimer's disease. J. Biol. Chem. 277, 40173-40176 (2002).
190. Palmblad M, Westlind-Danielsson A, Bergquist J. Oxidation of methionine 35 attenuates formation of amyloid b-peptide 1-40 oligomers. J. Biol. Chem. 22, 19506-19510 (2002).
191. Ciccotosto GD, Tew D, Curtain CC et al. Enhaced toxicity and cellular binding of a modified amyloid b peptide with methionine to valine substitution J. Biol. Chem. 279, 42528-42534 (2004).
192. Hou I, Zagorski MG. NMR reveals anomalous copper(II) binding to amyloid Ab peptide of Alzheimer's disease. J. Am. Chem. Soc. 128, 9260-9261 (2006).
193. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile palques in Alzheimer's disease: a central role for bound transition metals. J. Neurochem. 74, 270-279 (2000).
194. 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, 20466-20473 (2001).
195. Bitan G, Tarus B, Vollers SS et al. A molecular switch in amyloid assembly: Met35 and amyloid b-protein oligomerization. J. Am. Chem. Soc. 125, 15359-15365 (2003).
196. Liu G, Huang W, Moir RD et al. Metal exposure and Alzheimer's pathogenesis. J. Struct. Biol. 155, 45-51 (2006).
197. Mantyh P, Ghilardi JR, Rogers S et al. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of b-amyloid peptide. J. Neurochem. 61, 1171-1174 (1993).
198. Bush AI, Pettingeli WH, Multhaup G et al. Rapid induction of Alzheimer A-b amyloid formation by Zn. Science 265, 1464-1467 (1994).
199. Miura T, Suzuki K, Kohata N, Takeuchi H. Metal binding modes of Alhzeimer's amyloid b-peptide in insoluble aggregates and soluble complexes. Biochemistry 2000, 7024-7031 (2000).
200. 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, 32293-32299 (2001).
201. Cheng IH, Palop JJ, Esposito LA, Bien-Ly N, Yan F, Mucke L. Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat. Med. 10, 1190-1192 (2004).
202. Jin K, Galvan V, Xie L et al. Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice. Proc. Natl Acad. Sci. USA 101, 13363-13367 (2004)
203. Atwood CS, Moir RD, Huang X et al. Dramatic aggregation of Alzheimer's Ab by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 273, 12817-12826 (1998).
204. Morgan DM, Dong J, Jacob J. Metal switch for amyloid formation: insight into the structure of the nuclueus J. Am. Chem. Soc. 124, 12644-12645 (2002).
205. Raman B, Ban T, Yamaguchi K et al. Metal ion-dependent effects of clioqinol on the fibril growth of amyloid b peptide. J. Biol. Chem. 280, 16157-16162 (2005).
206. Dong J, Atwood CS, Anderson VE et al. Metal binding oxidation of Amyloid-b within Isolated senile plaque cores: Raman microscopy evidence. Biochemistry 42, 2768-2773 (2003).
207. 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, 1685-1691 (2003).
208. Da Silva GF, Ming LJ. Alzheimer's disease related copper(ii)-b-amyloid peptide exhibits phenol monooxygenase and catechol oxidase activities. Angew. Chem. 117, 5637-5640 (2005).
209. Raman B, Ban T, Yamaguchi K et al. Metal Ion-dependent effects of clioqinol on the fibril growth of amyloid b peptide. J. Biol. Chem. 280, 16157-16162 (2005).
210. Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT. Redox-active metals, oxidative stress, and Alzheimer's disease pathology. Ann. NY Acad. Sci. 1012, 153-163 (2004).
211. Raffa DF, Rikard GA, Rauk A. Ab initio modelling of the structure and redox behaviour of copper(I) bound to His-His model peptide: relevance to the b-amyloid peptide of Alzheimer's disease. J. Biol. Inorg. Chem. 12, 147-164 (2007).
212. Liu ST, Howlett G, Barrow CJ. Histidine-13 is a crucial residue in the Zn ion-induced aggregation of the Ab peptide of Alzheimer's disease Biochemistry 38, 9373-9378 (1999).
213. Syme CD, Nadal RC, Rigby SE, Viles JH. Copper binding to the amyloid-b (Ab) peptide associated with Alzheimer's disease. J. Biol. Chem. 279, 18169-18177 (2003).
214. Gomez-Balderas R, Raffa DF, Rickard GA, Brunelle P, Rauk A. Computational studies of Cu(II)/Met binding motif relevant for the chemsitry of Alzeimer's disease J. Phys. Chem. A 109, 5498-5508 (2005).
215. Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid b peptide is a critical requirement for the viability of central neurons. J. Neurosci. 23, 5531-5535 (2003).
216. Kontush A, Berndt C, Weber W et al. Amyloid-b is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med. 30, 119-128 (2001).
217. Butterfield DA, Boyd-Kimball D. The critical role of methionine 35 in Alzheimer's amyloid b-peptide (1-42)-induced oxidative stress and neurotoxicity. Biochim. Biophys. Acta 1703, 149-156 (2005).
218. Pollack SJ, Sadler J II, Hawtin SR, Tailor VJ, Shearman MS. Sulfonated dyes attenuate the toxic effects of b-amyloid in a structure-specific fashion. Neurosci. Lett. 197, 211-214 (1995).
219. Camilleri P, Haskins NJ, Howlett DR. b-cyclodextrin interacts with the Alzheimer amyloid b-A4 peptide. FEBS Lett. 341, 256-258 (1994).
220. Saloman AR, Marcinowski KJ, Friedland RP, Zagorski MG. Nicotine inhibits amyloid formation by the b-peptide. Biochemistry 35, 13568-13578 (1996).
221. Kirschner DA, Gross A, Hidalgo AR et al. Fiber diffraction as a screen for amyloid inhibitors. Curr. Alzheimer Res. 5, 288-307 (2008).
222. Szymanska I, Radecka H, Radecki J, Kaliszan R. Electrochemical impedance spectroscopy for study of amyloid b-peptide interactions with (-) nicotine ditartrate and (-) cotinine. Biosens. Bioelectron. 22, 9-10 (2007).
223. Barnham KJ, Kenche VB, Ciccotosto GD et al. Platinum-based inhibitors of amyloid-b as therapeutic agents for Alzheimer's disease. Proc. Natl Acad. Sci. USA 105, 6813-6818 (2008).
224. Moore SA, Huckerby TN, Gibson GL et al. Both the d-(+) and l-(-) enantiomers of nicotine inhibit Ab aggregation and cytotoxicity. Biochemistry 43, 819-826 (2004).
225. Zeng H, Zhang Y, Peng L-J et al. Nicotine and amyloid formation. Biol. Psychiatry 49, 248-257 (2001).
226. Hughes SR, Goyal S, Sun JE et al. Two-hybrid system as a model to study the interaction of b-amyloid peptide monomers. Proc. Natl Acad. Sci. USA 93, 2065-2070 (1996).
227. Peskind ER, Potkin SG, Nunzio P et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am. J. Geriatr. psychiatry 14, 704-715 (2006).
228. Raskind MA, Peskind ER, Wessel T et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 54, 2261-2268 (2000).
229. Gervais F, Paquette J, Morissette C et al. Targeting soluble Ab peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol. Aging 28, 537-547 (2007).
230. Fenili D, Brown M, Rappaport R, McLaurin J. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J. Mol. Med. 85, 603-611 (2007).
231. Doody RS, Gavrilova SI, Sano M et al. Effect of dimebon on cognition, activities of daily living, behaviour, global function in patients with mild-to-moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled study. Lancet 372, 207-215 (2008).
232. Kukar TL, Ladd TB, Bann MA et al. Substrate-targeting g-secretase modulators. Nature 453, 925-929 (2008).
233. 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. 8, 779-786 (2008).
234. 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, 1685-1691 (2003).
235. Korotkova O, Wolf E. Scattering matrix theory for stochastic scalar fields. Phys. Rev. E75, 056609-1-1 (2007).