Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics

Annual Review of Pharmacology and Toxicology

Volumn 43, Issue , 2003, Pages 545-584

  Selkoe, Dennis J ^a   Schenk, Dale ^b  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b ELAN PHARMACEUTICALS   (United States)

Author keywords

Amyloid protein; Immunization; Monoclonal antibodies; Protease inhibitors; Secretases

Indexed keywords

ALPHA TOCOPHEROL; AMYLOID BETA PEPTIDE[1-42]; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ASCORBIC ACID; ASPARTIC PROTEINASE INHIBITOR; BETA SECRETASE; CALCIUM CHANNEL AFFECTING AGENT; CARBAMAZEPINE; CHOLINESTERASE INHIBITOR; DONEPEZIL; GALANTAMINE; GAMMA SECRETASE; HALOPERIDOL; HYPOCHOLESTEROLEMIC AGENT; METHYLPHENIDATE; NONSTEROID ANTIINFLAMMATORY AGENT; OLANZAPINE; OM 992; PRESENILIN 1; PRESENILIN 2; QUETIAPINE; RISPERIDONE; RIVASTIGMINE; SELEGILINE; STATV; SYNTHETIC PEPTIDE; TACRINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROATE SEMISODIUM; ENZYME INHIBITOR;

ALLELE; ALZHEIMER DISEASE; AMINO ACID SEQUENCE; AUTOSOMAL DOMINANT DISORDER; CHOLINERGIC SYSTEM; CLINICAL TRIAL; DEMENTIA; DIARRHEA; DRUG MECHANISM; ENZYME SPECIFICITY; GENE IDENTIFICATION; GENETIC LINKAGE; GENETIC PREDISPOSITION; GENOTYPE; HUMAN; IMMUNIZATION; LIVER TOXICITY; MISSENSE MUTATION; NAUSEA; NEUROPATHOLOGY; NEUROPHARMACOLOGY; NONHUMAN; ONSET AGE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN DETERMINATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; SENILE PLAQUE; SIDE EFFECT; VOMITING; ANIMAL; DISEASE MODEL; GENETICS; IMMUNOLOGY; METABOLISM; METHODOLOGY; MOLECULAR BIOLOGY; MOUSE; PATHOPHYSIOLOGY;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; ANIMALS; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; HUMANS; IMMUNIZATION; MICE; MOLECULAR BIOLOGY;

EID: 0001181116     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.43.100901.140248     Document Type: Review

References (151)

1. Morris JC, Storandt M, McKeel DW, Rubin EH, Price JL, et al. 1996. Cerebral amyloid deposition and diffuse plaques in "normal" aging: evidence for presymptomatic and very mild Alzheimer's disease. Neurology 46:707-19
2. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. 1999. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56:303-38
3. Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P. 1995. Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol. Aging 16:285-98
4. Lemere CA, Blustzjan JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. 1996. Sequence of deposition of heterogeneous amyloid beta-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3:16-32
5. Verbeek MM, de Waal RM, Vinters HV. 2000. Cerebral Amyloid Angiopathy in Alzheimer's Disease and Related Disorders. Dordrecht, The Netherlands: Kluwer. 357 pp.
6. Davies P, Maloney AJ. 1976. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2:1403
7. Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. 1977. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J. Neurol. Sci. 34: 247-65
8. Bowen DM. 1977. Biochemistry of dementias. Proc. R. Soc. Med. 70:351-53
9. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. 1982. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237-39
10. Moller HJ. 1999. Reappraising neurotransmitter-based strategies. Eur. Neuropsychopharmacol. 9:S53-59
11. Davies P, Anderton B, Kirsch J, Konnerth A, Nitsch R, Sheetz M. 1998. First in, last one out: the role of gabaergic transmission in generation and degeneration. Prog. Neurobiol. 55:651-58
12. Bennett GW, Ballard TM, Watson CD, Fone KC. 1997. Effect of neuropeptides on cognitive function. Exp. Gerontol. 32: 451-69
13. Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, et al. 1987. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733-36
14. Selkoe DJ. 2001. Alzheimer's disease: genes, proteins and therapies. Physiol. Rev. 81:742-61
15. Haass C, Schlossmacher M, Hung AY, Vigo-Pelfrey C, Mellon A, et al. 1992. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359:322-25
16. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, et al. 1992. Isolation and quantitation of soluble Alzheimer's β-peptide from biological fluids. Nature 359:325-27
17. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, et al. 1992. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258: 126-29
18. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, et al. 1990. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248:1122-24
19. Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL. 1990. Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing. Science 248:492-95
20. Koo EH, Squazzo S. 1994. Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J. Biol. Chem. 269:17386-89
21. Perez RG, Soriano S, Hayes JD, Ostaszewski BL, Xia WM, et al. 1999. Mutagenesis identifies new signals for β-amyloid precursor protein endotycosis, turnover and the generation of secreted fragments, including Abeta42. J. Biol. Chem. 274:18851-56
22. Cao X, Sudhof TC. 2001. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293:115-20
23. Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. 2001. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem. 276:40288-92
24. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, et al. 2001. Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2:835-41
25. Smith RP, Higuchi DA, Broze GJ. 1990. Platelet coagulation factor XIa-inhibitor, a form of Alzheimer amyloid precursor protein. Science 248:1126-28
26. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, et al. 1991. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704-6
27. Hardy J. 1997. The Alzheimer family of diseases: many etiologies, one pathogenesis? Proc. Natl. Acad. Sci. USA 94:2095-97
28. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, et al. 1993. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:1977-81
29. Mahley RW, Rall SC Jr. 2000. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1:507-37
30. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, et al. 1994. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer's disease. Nat. Genet. 7:180-84
31. Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, et al. 1997. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet. 17:263-64
32. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, et al. 2000. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 97: 2892-97
33. Evans KC, Berger EP, Cho CG, Weisgraber KH, Lansbury PT Jr. 1995. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. Proc. Natl. Acad. Sci. USA 92:763-67
34. Ma J, Brewer HB Jr, Das S, Potter H. 1994. Amyloid-associated proteins alpha1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372: 92-94
35. Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, et al. 1995. Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein. N. Engl. J. Med. 333:1242-47
36. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, et al. 1993. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:9649-53
37. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard AB, et al. 1995. A familial Alzheimer's disease locus on chromosome 1. Science 269:970-73
38. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, et al. 1995. Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375:754-60
39. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, et al. 1995. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373: 523-27
40. Hsiao K, Chapman P, Nilsen S, Ekman C, Harigaya Y, et al. 1996. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274: 99-102
41. Borchelt DR, Thinakaran G, Echman CB, Lee MK, Davenport F, et al. 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate A beta1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005-13
42. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, et al. 1999. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96:3228-33
43. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, et al. 1998. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4:97-100
44. Wyss-Coray T, Masliah E, Mallory M, McConologue L, Johnson-Wood K, et al. 1997. Amyloidogenic role of cytokine TGF-beta-1 in transgenic mice and in Alzheimer's disease. Nature 389:603-6
45. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, et al. 2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487-91
46. Mayeux R, Sano M. 1999. Treatment of Alzheimer's disease. N. Engl. J. Med. 341:1670-79
47. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. 1992. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12:379-89
48. Butterfield DA, Drake J, Pocemich C, Castegna A. 2001. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide. Trends Mol. Med. 7:548-54
49. Chemy RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, et al. 2001. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30:665-76
50. Seubert P, Oltersdorf, Lee MG, Barbour R, Blomquist C, et al. 1993. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361:260-63
51. Howlett DR, Simmons DL, Dingwall C, Christie G. 2000. In search of an enzyme: the beta-secretase of Alzheimer's disease is an aspartic proteinase. Trends Neurosci. 23:565-70
52. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, et al. 1999. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-41
53. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, et al. 1999. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537-40
54. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, et al. 1999. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402:533-37
55. Hussain I, Powell DJ, Howlett DR, Tew DG, Meek TD, et al. 1999. Identification of a novel aspartic protease (Asp2) as beta-secretase. Mol. Cell. Neurosci. 14: 419-27
56. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. 2000. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 97:1456-60
57. Capell A, Steiner H, Willem M, Kaiser H, Meyer C, et al. 2000. Maturation and pro-peptide cleavage of beta-secretase. J. Biol. Chem. 275:30849-54
58. Yan R, Han P, Miao H, Greengard P, Xu H. 2001. The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta-amyloid precursor protein (APP) substrate. J. Biol. Chem. 276:36788-96
59. Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, et al. 2000. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol. Cell. Neurosci. 16:609-19
60. Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. 2000. BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc. Natl. Acad. Sci. USA 97:9712-17
61. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, et al. 2001. BACE knockout mice are healthy despite lacking primary-secretase activity in the brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10:1317-24
62. Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW. 2000. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase. J. Biol. Chem. 275:33729-37
63. Citron M, Oltersodrf T, Haass C, McConlogue L, Hung AY, et al. 1992. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production. Nature 360:672-74
64. Citron M, Teplow DB, Selkoe DJ. 1995. Generation of amyloid beta protein from its precursor is sequence specific. Neuron 14:661-70
65. Sauder JM, Arthur JW, Dunbrack RL Jr. 2000. Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase. J. Mol. Biol. 300:241-48
66. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, et al. 2000. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290:150-53
67. Gruninger-Leitch F, Schlatter D, Kung E, Nelbock P, Dobeli H. 2002. Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J. Biol. Chem. 277:4687-93
68. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. 2001. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 4:231-32
69. Cai HB, Wang YS, McCarthy D, Wen HJ, Borchelt DR, et al. 2001. BACE1 is the major beta-secretase for generation of A beta peptides by neurons. Nat. Neurosci. 4:233-34
70. Phimister B. 2000. Four companies announce discovery of beta-secretase gene. Nat. Biotechnol. 18:16
71. Ghosh AK, Shin D, Downs D, Koelsch G, Lin X, et al. 2000. Design of potent inhibitors of human brain memapsin 2 (beta-secretase). J. Am. Chem. Soc. 123:3522-23
72. Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, et al. 2001. Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase). J. Med. Chem. 44:2865-68
73. Brown MS, Ye J, Rawson RB, Goldstein JL. 2000. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100:391-98
74. Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J, et al. 1997. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell 1:47-57
75. Urban S, Lee JR, Freeman M. 2001. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107:173-82
76. Scheuner D, Eckman C, Jensen M, Song X, Citron M, et al. 1996. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2:864-70
77. Levitan D, Greenwald I. 1995. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377: 351-54
78. Shen J, Bronson RT, Chen DF, Xia WM, Selkoe DJ, Tonegawa S. 1997. Skeletal and CNS defects in presenilin-1 deficient mice. Cell 89:629-39
79. Wong PC, Zhen H, Chen H, Becher MW, Sirinathsinghji DJS, et al. 1997. Presenilin 1 is required for Notch 1 and D111 expression in the paraxial mesoderm. Nature 397:288-92
80. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Gundula G, et al. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387-90
81. Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. 2000. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2:461-62
82. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, et al. 2000. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2:463-65
83. Wolfe MS, Xia W, Ostaszewski BL, Diehl, TS, Kimberly WT, Selkoe, DJ. 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398:513-517
84. Xia WM, Zhang JM, Perez R, Koo EH, Selkoe DJ. 1997. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 94:8208-13
85. Xia WM, Ray WJ, Ostaszewski BL, Rahmati T, Kimberly WT, et al. 2000. Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid β-protein generation. Proc. Natl. Acad. Sci. USA 97:9299-304
86. Xia W, Zhang JM, Ostaszewski BL, Kimberly WT, Seubert P, et al. 1998. Presenilin 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid β-protein in ER and Golgi. Biochemistry 37:16465-71
87. Wolfe MS, Citron M, Diehl TS, Xia WM, Donkor IO, Selkoe DJ. 1998. A substrate-based difluoro ketone selectively inhibits Alzheimer's gamma-secretase activity. J. Med. Chem. 41:6-9
88. Wolfe MS, Xia WM, Moore CL, Leatherwood DD, Ostaszewski BL, et al. 1999. Peptidomimetic probes and molecular modeling suggest Alzheimer's γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38:4720-27
89. Li YM, Lai MT, Xu M, Huang Q, Di-Muzio-Mower J, et al. 2000. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. USA 97:6138-43
90. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, et al. 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat. Cell Biol. 2:428-34
91. Li YM, Xu M, Lai MT, Huang Q, Castro JL, et al. 2000. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689-94
92. Kimberly WT, Xia WM, Rahmati R, Wolfe MS, Selkoe DJ. 2000. The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation. J. Biol. Chem. 275:3173-78
93. LaPointe CF, Taylor RK. 2000. The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J. Biol. Chem. 275:1502-10
94. Steiner H, Kostka M, Romig H, Basset G, Pesold B, et al. 2000. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat. Cell Biol. 2:848-51
95. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. 2002. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296:2215-18
96. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, et al. 1996. Endoprotreolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181-90
97. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, et al. 2000. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407:48-54
98. Deleted in proof
99. Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, et al. 1998. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J. Biol. Chem. 273:16470-75
100. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, et al. 2002. Activity dependent isolation of the presenilin-gamma secretase complex reveals nicastrin and a gamma substrate. Proc. Natl. Acad. Sci. USA 99:2720-25
101. Goutte C, Tsunozaki M, Hale VA, Priess JR. 2002. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl. Acad. Sci. USA 99:775-79
102. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, et al. 2002. aph-1 and pen-2 are required for Notch pathway signaling, gamma secretase cleavage of βAPP and presenilin protein accumulation. Dev. Cell. 3:85-97
103. Lichtenthaler SF, Wang R, Grimm H, Uljon SN, Masters CL, Beyreuther K. 1999. Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc. Natl. Acad. Sci. USA 96:3053-58
104. Lichtenthaler SF, Beher D, Grimm HS, Wang R, Shearman MS, et al. 2002. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. Proc. Natl. Acad. Sci. USA 99:1365-70
105. Saura CA, Tomita T, Soriano S, Takahashi M, Leem JY, et al. 2000. The nonconserved hydrophilic loop domain of presenilin (PS) is not required for PS endoproteolysis or enhanced A beta 42 production mediated by familial early onset Alzheimer's disease-linked PS variants. J. Biol. Chem. 275:17136-42
106. Struhl G, Adachi A. 2000. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol. Cell 6:625-36
107. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, et al. 2001. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 76:173-81
108. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, et al. 1999. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155:853-62
109. McLean CA, Cherny RA, Fraser FW, Smith MJ, Beyreuther K, et al. 1999. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46:860-66
110. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, et al. 1998. Diffusible, nonfibrillar ligands derived from A betal -42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95:6448-53
111. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, et al. 1999. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19:8876-84
112. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, et al. 2002. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-39
113. Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, et al. 1999. Presenilin 1 controls γ-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons. J. Cell Biol. 147:277-94
114. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, et al. 2001. A subset of NSAIDs lower amyloidogenic A beta42 independently of cyclooxygenase activity. Nature 414:212-26
115. in t'Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, et al. 2001. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345:1515-21
116. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, et al. 1999. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173-77
117. Pepys MB, Herbetrt J, Hutchinson WL, Tennent GA, Lachmann HJ, et al. 2002. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417:254-59
118. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, et al. 2000. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408:982-85
119. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, et al. 2000. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408:979-82
120. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, et al. 2000. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann. Neurol. 48:553-55
121. Bard F, Cannon C, Barbour R, Burke RL, Games D, et al. 2000. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6:916-19
122. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 2001. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98:8850-55
123. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. 2002. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295:2264-67
124. Solomon B, Koppel R, Hanan E, Katzav T. 1996. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer β-amyloid peptide. Proc. Natl. Acad. Sci. USA 93:452-55
125. Solomon B, Koppel R, Frankel D, Hanan-Aharon E. 1997. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc. Natl. Acad. Sci. USA 94: 4109-12
126. Higgins LS, Murphy GM Jr, Forno LS, Catalano R, Cordell B. 1996. P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain. Am. J. Pathol. 149:585-96
127. Lalowski M, Golabek A, Lemere CA, Selkoe DJ, Wisniewski HM, et al. 1996. The "nonamyloidogenic" p3 fragment (amyloid beta17-42) is a major constituent of Down's syndrome cerebellar preamyloid. J. Biol. Chem. 271:33623-31
128. Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. 1992. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304-7
129. Buxbaum JD, Koo EH, Greengard P. 1993. Protein phosphorylation inhibits production of Alzheimer amyloid β/A4 peptide. Proc. Natl. Acad. Sci. USA 90: 9195-98
130. Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, et al. 1993. Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J. Biol. Chem. 268:22959-62
131. Beach TG, Kuo YM, Schwab C, Walker DG, Roher AE. 2001. Reduction of cortical amyloid beta levels in guinea pig brain after systemic administration of physostigmine. Neurosci. Lett. 310:21-24
132. Beach TG, Walker DG, Potter PE, Sue LI, Fisher A. 2001. Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res. 905:220-23
133. Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. 2000. The selective muscarinic M1 agonist AF102B decreases levels of total A beta in cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 48:913-18
134. Lee RK, Wurtman RJ. 1997. Metabotropic glutamate receptors increase amyloid precursor protein processing in astrocytes: inhibition by cyclic AMP. J. Neurochem. 68:1830-35
135. Nitsch RM, Deng M, Growdon JH, Wurtman RJ. 1996. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J. Biol. Chem. 271:4188-94
136. Nitsch RM, Kim C, Growdon JH. 1998. Vasopressin and bradykinin regulate secretory processing of the amyloid protein precursor of Alzheimer's disease. Neurochem. Res. 23:807-14
137. Farber SA, Nitsch RM, Schulz JG, Wurtman RJ. 1995. Regulated secretion of beta-amyloid precursor protein in rat brain. J. Neurosci. 15:7442-51
138. Sing CF, Davignon J. 1985. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am. J. Hum. Genet. 37:268-85
139. Simons K, Ikonen E. 1997. Functional rafts in cell membranes. Nature 387:569-72
140. Lee SJ, Liyanage U, Bickel PE, Xia WM, Lansbury PT, Kosik KS. 1998. A detergent-insoluble membrane compartment contains Aβ in vivo. Nat. Med. 4:730-34
141. Yanagisawa K, Odaka A, Suzuki N, Ihara Y. 1995. GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer's disease. Nat. Med. 1:1062-66
142. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. 1998. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc. Natl. Acad. Sci. USA 95:6460-64
143. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. 2001. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc. Natl. Acad. Sci. USA 98:5815-20
144. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, et al. 2001. Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides A beta 42 and A beta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98: 5856-61
145. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmid SD, et al. 2001. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 8:890-99
146. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, et al. 2000. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7: 321-31
147. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. 2000. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57:1439-43
148. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. 2000. Statins and the risk of dementia. Lancet 356:1627-31
149. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, et al. 2002. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch. Neurol. 59:223-27
150. Glenner GG, Wong CW. 1984. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120:885-90
151. Dodart JC, Bales KR, Gannon K-S, Greene SJ, DeMattos RB, Mathis C, et al. 2002. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat. Neurosci. 5:452-57