Alzheimer's disease: Genetic studies and transgenic models

Annual Review of Genetics

Volumn 32, Issue , 1998, Pages 461-493

  Price, Donald L ^a   Tanzi, Rudolph E ^b   Borchelt, David R ^a   Sisodia, Sangram S ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Amyloid precursor protein; Dystrophic neurites; Presenilin 1 and 2; Senile dementia; Tg mice

Indexed keywords

PRESENILIN 1; PRESENILIN 2;

ALZHEIMER DISEASE; ANIMAL MODEL; GENE LOCUS; MOUSE; NERVE DEGENERATION; NEURITE; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSGENIC MOUSE;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; APOLIPOPROTEINS E; CAENORHABDITIS ELEGANS; DISEASE MODELS, ANIMAL; HUMANS; MEMBRANE PROTEINS; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; MUTATION; PHENOTYPE; PRESENILIN-1; PRESENILIN-2;

ANIMALIA; MUS MUSCULUS;

EID: 0032413192     PISSN: 00664197     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.genet.32.1.461     Document Type: Review

References (227)

1. Deleted in proof
2. 1-antichymotrypsin, in the brain amyloid deposits of Alzheimer's disease. Cell 52: 487-501
3. 1-Antichymotrypsin is present together with the β-protein in monkey brain amyloid deposits. Neuroscience 32:715-20
4. Albert MS. 1996. Cognitive and neurobiologic markers of early Alzheimer disease. Proc. Natl. Acad. Sci. USA 93: 13547-51
5. Ammassari-Teule M, Hoffman H-J, Rossi-Arnaud C. 1993. Learning in inbred mice: strain-specific abilities across three radial maze problems. Behav. Genet. 23:405-12
6. Anderton BH, Breinburg D, Downes MJ, Green PJ, Tomlinson BE, et al. 1982. Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature 298:84-86
7. Arnold SE, HymanBT, Flory J, Damasio AR, Van Hoesen GW. 1991. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1:103-16
8. Artavanis-Tsakonas S, Matsuno K, Fortini ME. 1995. Notch signaling. Science 268:225-32
9. Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, et al. 1997. Lack of apolipoprotein E dramatically reduces amyloid B-peptide deposition. Nat. Genet. 17:263-64
10. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grünberg J, et al. 1997. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1:149-59
11. Berg L, Morris JC. 1994. Diagnosis. See Ref. 193a, pp. 9-25
12. Blacker D, Haines JL, Rodes L, Terwedow H, Go RCP, et al. 1997. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology 48:139-47
13. Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, et al. 1998. Alpha-2-macroglobulin is associated with Alzheimer's disease. Nat. Genet. In press
14. Blessed G, Tomlinson BE, Roth M. 1968. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br. J. Psychiatry 114:797-811
15. Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, et al. 1996. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet. Anal. Biomed. Eng. 13:159-63
16. Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales VB, et al. 1997. Accelerated amyloid deposition in the brains of transgenic mice co-expressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939-45
17. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, et al. 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005-13
18. Borth W. 1992. Alpha 2-macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J. 6:3345-53
19. Braak H. Braak E. 1994. Pathology of Alzheimer's disease. In Neurodegenerative Diseases, ed. DB Calne, 35:585-613. Philadelphia, PA: Saunders
20. Buxbaum JD, Christensen JL, Ruefli AA. Greengard P, Loring JF. 1993. Expression of APP in brains of transgenic mice containing the entire human APP gene. Biochem. Biophys. Res. Commun. 197:639-45
21. Carlson GA, Borchelt DR, Dake A, Turner S, Danielson V, et al. 1997. Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum. Mol. Genet. 6:1951-59
22. Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, et al. 1991. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353:844-46
23. Chartier-Harlin M-C, Parfitt M, Legrain S, et al. 1994. Apolipoprotein E, ε4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q 13.2 chromosomal region. Hum. Mol. Genet. 3:569-74
24. Citron M, Oltersdorf 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
25. Citron M, Westaway D, Xia W, Carlson G, Diehl T, et al. 1997. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med. 3:67-72
26. Conlon RA, Reaume AG, Rossant J. 1995. Notch 1 is required for the coordinate segmentation of somites. Development 121:1533-45
27. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, et al. 1997. Alzheimer's Aβ(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat. Med. 3:1021-23
28. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. 1993. Gene dose of apolipoprotein-E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-23
29. Crook R, Chen LS, Bende SM, LaFerla FM. 1998. A variant of Alzheimer's disease wtih spastic paraphrasis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat. Med. 4:1-4
30. Cruts M, van Duijn CM, Backhovens H, van den Broeck M, Wehnert A, et al. 1998. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum. Mol. Genet. 71:43-51
31. Davis JA, Naruse S, Chen H, Eckman C, Younkin S, et al. 1998. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 20: 603-9
32. Davis RE, Miller S, Herrnstadt C, Ghosh SS, Fahy E. et al. 1997. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:4526-31
33. Delacourte A, Sereant N, Wattez A, Gauvreau D, Robitaille Y. 1998. Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their τ isoform distribution and phosphorylation. Ann. Neurol. 43:193-204
34. De Strooper B, Saftig P, Craessaorts K, et al. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387-90
35. Dickson DW. 1997. Neurodegenerative diseases with cytoskeletal pathology: a biochemical classification. Ann. Neurol. 42:541-44
36. Doan A, Thinakaran G, Borchelt DR, Slunt HH, Ratovitsky T, et al. 1996. Protein topology of presenilin 1. Neuron 17: 1023-30
37. Drachman DA. 1997. Aging and the brain: a new frontier. Ann. Neurol. 42: 819-28
38. Du Y. 1997. Alpha-2-macroglobulin as a beta-amyloid peptide-binding plasma protease. J. Neurochem. 69:299-305
39. Duff K, Eckman C, Zehr C, Yu X, Prada C-M, et al. 1996. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin I. Nature 383:710-13
40. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, et al. 1990. Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248: 1122-24
41. Evans DA, Beckett LA, Field TS, Feng L, Albert MS, et al. 1997. Apolipoprotein E ε4 and incidence of Alzheimer disease in a community population of older persons. JAMA 277:822-24
42. Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, et al. 1989. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA 262:2551-56
43. Farlow MR. 1997. Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology 48:530-34
44. Feany MB, Dickson DW. 1996. Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann. Neurol. 40:139-48
45. Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, D'Amato CJ, et al. 1997. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a consensus conference. Ann. Neurol. 41: 706-15
46. Francis PT, Cross AJ, Bowen DM. 1994. Neurotransmitters and neuropeptides. See Ref. 193a, pp. 247-61
47. Galasko D, Saitoh T, Xia Y, Thai LJ, Katzman R, et al. 1994. The apolipoprotein E allele ε4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease. Neurology 44:1950-51
48. 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
49. Gerlai R. 1996. Gene-targeting studies of mammalian behavior: Is it the mutation or the background phenotype? Trends Neurosci. 19:177-81
50. Geula C, Mesulam M-M. 1994. Cholinergic systems and related neuropathological predilection patterns in Alzheimer disease. See Ref. 193a, pp. 263-91
51. Glenner GG, Wong CW. 1984. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophvs. Res. Commun. 120: 885-90
52. Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, et al. 1991. Segregation of a missense mutalion in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704-6
53. Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, et al. 1996. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550-53
54. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. 1992. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159-68
55. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. 1987. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235:877-80
56. Gómez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, et al. 1996. Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer disease. Ann. Neurol. 39:62-70
57. Griffin WST, Sheng JG, Roberts GW, Mrak RE 1995. Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J. Neuropathol. Exp. Neurol. 54:276-81
58. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung Y-C, Zaidi MS, et al. 1986. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261:6084-89
59. Haass C, Lemere CA, Capell A, Citron M, Seubert P, et al. 1995. The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1:1291-96
60. Haass C, Selkoe DJ. 1993. Cellular processing of β-amyloid precursor and the genesis of amyloid β-peptide. Cell 75:1039-42
61. Hardy J. 1997. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20:154-59
62. Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N. et al. 1997. Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides. Nat. Med. 3:1016-20
63. Hendricks L, van Duijn CM, Cras P, Cruts M, Van Hul W, et al. 1992. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nat. Genet. 1:218-21
64. Higgins LS, Holtzman DM, Rabin J, Mobley WC, Cordell B. 1994. Transgenic mouse brain histopathology resembles early Alzheimer's disease. Ann. Neurol. 35:598-607
65. Hirano M, Shtilbans A, Mayeux R, et al. 1997. Apparent mtDNA heteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes. Proc. Natl. Acad. Sci. USA 94: 14894-99
66. 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
67. Hopkins SJ, Rothwell NJ. 1995. Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci. 18:83-88
68. Hrabede Angelis M, McIntyre J, Gossler A. 1997. Maintenance of somite borders in mice requires the Delta homologue DIII. Nature 386:717-21
69. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y. et al. 1996. Correlative memory deficts. Aβ elevation and amyloid plaques in transgenic mice. Science 274:99-102
70. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, et al. 1997. Measuring memory in a mouse model of Alzheimer's disease. Science 277:840-41
71. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, et al. 1995. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15:1203-18
72. Hughes SR. 1997. Alpha-2-macroglobulin associates with β-amyloid peptide and prevents fibril formation. J. Neurochem. 69:299-305
73. Hyman BT, Gomez-Isla T, Briggs M, Chung H, Nichols S, et al. 1996. Apolipoprotein E and cognitive change in an elderly population. Ann. Neurol. 40:55-66
74. Sw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56:965-73
75. Ishii K, Ii K, Hasegawa T, Shoji S, Doi A, et al. 1997. Increased Aβ 42(43)-plaque depostion in early-onset familial Alzheimer's disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS-1 gene. Neurosci. Lett. 228:17-20
76. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, et al. 1994. Visualization of Aβ42(43)-positive and Aβ40-positive senile plaques with end-specific A β-monoclonal antibodies: evidence that an initially deposited Aβ species is Aβ1-42(43). Neuron 13:45-53
77. Jagust WJ. 1998. Neuroimaging of dementing disorders. See Ref. 113a, 2:25-55
78. Jarrett JT, Lansbury PT Jr. 1993. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73: 1055-58
79. Johnson SA, Lampert-Etchells M, Pasinetti GM, Rozovsky I, Finch CE. 1992. Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning. Neurobiol. Aging 13:641-48
80. Jucker M, Ingram DK. 1997. Murine models of brain aging and age-related neurodegenerative diseases. Behav. Brain Res. 85:1-25
81. Kamboh MI, Sanghera DK, Ferrell RE. DeKosky ST. 1995. APOE4-associated Alzheimer's disease risk is modified by alpha 1-antichymotripsin polymorphism. Nat. Genet. 10:486-88
82. Kammesheidt A, Boyce FM, Spanoyannis AF, Cummings BJ, Ortegón M, et al. 1992. Deposition of β/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyterminal fragment of the Alzheimer amyloid precursor in the brain. Proc. Natl. Acad. Sci. USA 89:10857-61
83. Kang DE, Saitoh T, Chen X, Xia Y, Masliah E, et al. 1997. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology 49:56-61
84. 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
85. Kim T-W, Tanzi RE. 1997. Presenilins and Alzheimer's disease. Curr. Opin. Neurobiol. 7:683-88
86. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, et al. 1990. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc. Natl. Acad. Sci. USA 87:1561-65
87. Koo EH, Squazzo SL, Selkoe DJ, Koo CH. 1996. Trafficking of cell-surface amyloid β-protein precursor. 1. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody. J. Cell Sci. 109:991-98
88. Kounnas MZ, Moir RD, Rebeck GW, Bush AI, Argraves WS, et al. 1995. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation. Cell 82:331-40
89. Kwok J, Taddei K, Hallupp M, Fisher C, Brooks W, et al. 1997. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 8:1537-42
90. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G. 1995. The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat. Genet. 9:21-30
91. Lamb BT, Call LM, Slunt HH, Bardel KA, Lawler AM, et al. 1997. Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum. Mol. Genet. 6:1535-41
92. Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, et al. 1993. Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice. Nat. Genet. 5:22-30
93. Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, et al. 1998. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease. Hum. Mol. Genet. 7:533-40
94. Lambert JC, Perez-Tur J, Dupire MJ, Galasko D, Amouyel P, et al. 1997. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Hum. Mol. Genet. 6:2151-54
95. Lansbury PT Jr. 1997. Structural neurology: Are seeds at the root of neuronal degeneration? Neuron 19:1151-54
96. Lee MK, Borchelt DR, Kim G, Thinakaran G, Slunt HH, et al. 1997. Hyper-accumulation of FAD-linked presenilin 1 variants in vivo. Nat. Med. 3:756-60
97. Lee MK, Slunt HH, Martin LJ, Thinakaran G, Kim G, et al. 1996. Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. J. Neurosci. 16:7513-25
98. Lee VMY, Balin BJ, Otvos L Jr, Trojanowski JQ. 1991. A68: a major sub-unit of paired helical filaments and derivatized forms of normal tau. Science 251:675-78
99. Lehmann DJ, Johnston C, Smith AD. 1997. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. Hum. Mol. Genet. 6:1933-36
100. Lehmann S, Chiesa R, Harris DA. 1997. Evidence for a six-transmembrane domain structure of presenilin 1. J. Biol. Chem. 272:12047-51
101. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC. et al. 1996. Sequence of deposition of heterogeneous amyloid β-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3:16-32
102. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, et al. 1996. The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat. Med. 2:1146-50
103. Lendon CL, Talbot CJ, Craddock NJ, Han SW, Wragg M, et al. 1997. Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population. Neunisci. Lett. 222:187-90
104. Lennox GG, Lowe JS. 1998. Dementia with Lewy bodies. See Ref. 113a, 10:181-92
105. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, et al. 1996. Assessment of normal and mutant human presenilin function in Caenorhabdilis elegans. Proc. Natl. Acad. Sci. USA 93:14940-44
106. Levitan D, Greenwald I. 1995. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegant S182 Alzheimer's disease gene. Nature 377:351-54
107. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, et al. 1990. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrage, Dutch type. Science 248:1124-26
108. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, et al. 1995. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973-77
109. Li X, Greenwald I. 1996. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17:1015-21
110. Lopes MB, Bogaev CA, Gonias SL, Vandenberg SR. 1993. Expression of alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein is increased in reactive and neoplastic glial cells. FEBS Lett.
111. Lue L-F, Brachova L, Civin WH, Rogers J. 1996. Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J. Neuropathol. Exp. Neurol. 55:1083-88
112. Mackenzie IRA, Hao C, Munoz DG. 1995. Role of microglia in senile plaques formation. Neurobiol. Aging 16:797-804
113. 42(43). Ann. Neurol. 40:149-56
114. Mann DMA, Iwatsubo T, Fukomoto H, Ihara Y, Odaka A, et al. 1995. Microglial cells and amyloid β prolein (Aβ) deposition: association with Aβ40-containing plaques. Acta Neuropathol. 90:472-77
115. Mann DMA, Iwatsubo T, Nochlin D, Sumi SM, Levy-Lahad E, et al. 1997. Amyloid (Aβ) deposition in chromosome 1-linked Alzheimer's disease: the Volga German families. Ann. Neurol. 41:52-57
116. Markesbery WR, ed. 1998. Neuropathology of Dementing Disorders. London: Arnold
117. Markesbery WR. 1998. Pick's disease. See Ref. 113a, 7:142-57
118. Markesbery WR. 1998. Vascular dementia. See Ref. 113a, 15:293-311
119. Martin LJ, Sisodia SS, Koo EH, Cork LC, Dellovade TL, et al. 1991. Amyloid precursor protein in aged nonhuman primates. Proc. Natl. Acad. Sci. USA 88:1461-65
120. Masliah E. 1998. The role of synaptic proteins in neurodegenerative disorders. Neurosci. News 1:14-20
121. Masliah E, Ellisman M, Carragher B, Mallory M, Young S, et al. 1992. Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease. J. Neuropathol. Exp. Neurol. 51:404-14
122. Masliah E, Hansen L, Albright T, Mallory M, Terry RD. 1991. Immunoelectron microscopic study of synaptic pathology in Alzheimer's disease. Acta Neuropathol. 81:428-33
123. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, et al. 1996. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16:5795-811
124. Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN. et al. 1985. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 4:2757-63
125. Mattson MP. 1997. Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77:1081-132
126. Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, et al. 1998. Utility of the apolipoprotein-E genotype in the diagnosis of Alzheimer's disease. N. Engl. J. Med. 338:506-11
127. Mayeux R, Stern Y, Ottman R, Tatemichi TK, Tang M-X, et al. 1993. The apolipoprotein ε4 allele in patients with Alzheimer's disease. Ann. Neurol. 34: 752-54
128. McGeer PL, Itagaki S, Tago H, McGeer EG. 1987. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett. 79:195-200
129. McGeer PL, McGeer EG. 1995. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Rev. 21:195-218
130. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, et al. 1996. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113-24
131. McKhann G, Drachman D, Folstein M, Katzman R, Price D, et al. 1984. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939-44
132. Mesulam M-M, Geula C. 1994. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann. Neurol. 36:722-27
133. Meyer MR, Tschanz JT, Norton MC, et al. 1998. ApoE polymorphism predicts when - not whether - individuals are predisposed to develop Alzheimer's disease. Nat. Genet. In press
134. Montoya SE, Aston CE, DeKosky ST, Kamboh MI, Lazo JS, et al. 1998. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease. Nat. Genet. 18:211-12
135. Moran PM, Higgins LS, Cordell B, Moser PC. 1995. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 92:5341-15
136. Morrison JH, Hof PR. 1997. Life and death of neurons in the aging brain. Science 278:412-19
137. Mullan M, Crawford F, Axelman K, Houlden H, Lillius L, et al. 1992. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1:345-47
138. Murrell J, Farlow M, Ghetti B, Benson MD. 1991. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254:97-99
139. Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, et al. 1997. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387:500-5
140. Namekata K, Imagawa M, Terashi A, Ohta S, Oyama F, et al. 1997. Association of transferrin C2 allele with late-onset Alzheimer's disease. Hum. Genet. 101:126-29
141. Narita M, Holtzman DM, Schwartz AL, Bu G. 1997. Alpha-2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J. Neurochem. 69:1904-11
142. Neve RL, Kammesheidt A, Hohmann CF. 1992. Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo. Proc. Natl. Acad. Sci. USA 89:3448-52
143. Okuizumi K, Onodera O, Namba Y, Ikeda K. Yamamoto T, et al. 1995. Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease. Nat. Genet. 11:207-9
144. Olshansky SJ, Carnes BA, Cassel CK. 1993. The aging of the human species. Sci. Am. 268:46-52
145. Owen EH, Logue SF, Rasmussen DL, Wehner JM. 1997. Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: implications of genetic background for single gene mutations and quantitative trait loci analyses. Neuroscience 80:1087-99
146. Pappolla MA, Chyan Y-J, Omar RA, Hsiao K, Perry G, et al. 1998. Evidence of oxidative stress and m vivo neurotoxicity of β-amyloid in a transgenic mouse model of Alzheimer's disease. A chronic oxidative paradigm for testing antioxidant therapies in vivo. Am. J. Pathol. 152:871-77
147. Paylor R, Baskall L, Wehner JM. 1993. Behavioral dissociations between C57BL/6 and DBA/2 mice on learning and memory tasks: a hippocampal-dysfunction hypothesis. Psychobiology 21:11-26
148. Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, et al. 1995. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7:297-301
149. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, et al. 1997. Complete genomic screen in late-onset familial Alzheimer disease. JAMA 278:1237-41
150. Perry G, Friedman R, Shaw G, Chau V. 1987. Ubiquitin is detected in neurofibrillary tangles and senile plaque neuntes of Alzheimer disease brains. Proc. Natl. Acad. Sci. USA 84:3033-36
151. Pitschke M, Prior R, Haupt M, Riesner D. 1998. Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer's patients by fluorescence correlation spectroscopy. Nat. Med. 4:832-34
152. 299 and occur as stable N-and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol. Dis. 3:325-37
153. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, et al. 1998. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43:815-25
154. Price DL, Kawas CH, Sisodia SS. 1998. Aging of the brain and dementia of the Alzheimer's type. In Principles of Neural Science, ed. ER Kandel, JH Schwartz, TM Jessell. New York: Elsevier. In press
155. Price DL, Sisodia SS. 1998. Mutant genes in familial Alzheimer's disease and transgenic models. Annu. Rev. Neurosci. 21:479-505
156. Qian S, Jiang P, Guan X, Singh G, Trumbauer M, et al. 1998. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aß1-42/43 expression. Neuron 20:611-17
157. 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Ann. Neurol. 37:211-17
158. Rebeck GW, Reiter JS, Strickland DK, Hyman BT. 1993. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 11:575-80
159. Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM. 1987. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc. Natl. Acad. Sci. USA 84:4190-94
160. Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E. et al. 1995. Levels and alternative splicing of amyloid β protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease. J. Biol. Chem. 270:28257-67
161. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M. et al. 1995. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome I related to the Alzheimer's disease type 3 gene. Nature 376:775-78
162. Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, et al. 1992. Complement activation by β-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 89:10016-20
163. Rogers J, Luber-Narod J, Styren SC, Civin WH. 1988. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol. Aging 9:339-49
164. Roher A, Wolfe D, Palutke M, KuKurga D. 1986. Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proc. Natl. Acad. Sci. USA 83:2662-66
165. Rothwell NJ, Hopkins SJ. 1995. Cytokines and the nervous system. II: Actions and mechanisms of action. Trends Neurosci. 18:130-36
166. Roullet P, Lassalle JM. 1995. Radial maze learning using exclusively distant visual cues reveals learners and non-learners among inbred mouse strains. Physiol. Behav. 58:1189-95
167. Routtenberg A. 1997. Measuring memory in a mouse model of Alzheimer's disease. Science 277:839-40
168. N3(pE), in senile plaques. Neuron 14:457-66
169. St George-Hyslop PH. 1998. Genetics of Alzheimer's disease. See Ref. 113a, 5:106-20
170. St George-Hyslop PH, Haines P, Rogaev E, Mortilla M, Vaula G, et al. 1992. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat. Genet. 2:330-34
171. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, et al. 1987. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235:885-90
172. Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA. et al. 1993. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467-72
173. Schellenberg GD. 1995. Progress in Alzheimer's disease genetics. Curr. Opin. Neurol. 8:262-67
174. 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
175. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, et al. 1993. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer's disease. Proc. Natl. Acad. Sci. USA 90:9649-53
176. Schmidt ML, Lee VMY, Forman M, Chiu T-S, Trojanowski JQ. 1997. Monoclonal antibodies to a 100-kd protein reveal abundant Aβ-negative plaques throughout gray matter of Alzheimer's disease brains. Am. J. Pathol. 151:69-80
177. Schofield P, Mayeux R. 1998. Alzheimer's disease: clinical features, diagnosis and epidemiology. See Ref. 113a, 4:89-105
178. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, et al. 1997. Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89:629-39
179. + astrocytes with neurofibrillary tangle stages. J. Neuropathol. Exp. Neurol. 56: 285-90
180. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, et al. 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754-60
181. Sisodia SS. 1992. β-amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. USA 89:6075-79
182. Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL. 1990. Evidence that β-amyloid protein in Alzheimer's disease is not derived by normal processing. Science 248:492-95
183. Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL. 1993. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J. Neurosci. 13:3136-42
184. Slunt HH, Thinakaran G, von Koch C, Lo ACY, Tanzi RE, et al. 1994. Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP). J. Biol. Chem. 269:2637-44
185. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PLR, et al. 1998. Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress. J. Neurochem. 70:2212-15
186. Smith MA, Rudnicka-Nawrot M, Richey PL, Praprotnik D, Mulvihill P, et al. 1995. Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J. Neurochem. 64:2660-66
187. Smith MA, Sayre LM, Monnier VM, Perry G. 1995. Radical AGEing in Alzheimer's disease. Trends Neurosci. 18:172-76
188. Snow AD, Mar H, Nochlin D, Kimata K, Kato M, et al. 1988. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. Am. J. Pathol. 133:456-63
189. 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
190. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold K-H, Mistl C, et al. 1997. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Nail. Acad. Sci. USA 94:13287-92
191. 717) mutants. Science 264:1336-40
192. Sze C-I, Troncoso JC, Kawas CH, Mouton PR, Price DL, et al. 1997. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 56: 933-44
193. Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St George-Hyslop P, et al. 1987. Amyloid β protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235:880-84
194. Tanzi RE, McClatchey AI, Lampert ED, Villa-Komaroff L, Gusella JF, et al. 1988. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature 331:528-30
195. Tanzi RE, St George-Hyslop PH, Haines JL, Polinsky RJ, Nee L, et al. 1987. The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid β-protein gene. Nature 329:156-57
196. Tanzi RE, Vaula G, Romano DM, Mortilla M, Huang TL, et al. 1992. Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am. J. Hum. Genet. 51:273-82
197. Terry RD, Katzman R, Bick KL, eds. 1994. Alzheimer Disease. New York: Raven
198. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, et al. 1996. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181-90
199. ThinakaranG, Regard JB, Bouton CML, Harris CL, Price DL, et al. 1998. Stable association of presenilin derivatives and absence of presenilin interactions with APP. Neurobiol. Dis. 4:438-53
200. Trojanowski JQ, Growdon JH. 1998. A new consensus report on biomarkers for the early antemortem diagnosis of Alzheimer disease: current status, relevance to drug discovery, and recommendations for future research. J. Neuropathol. Exp. Neurol. 57:643-44
201. Troncoso JC, Sukhov RR, Kawas CH, Koliatsos VE. 1996. In situ labeling of dying cortical neurons in normal aging and in Alzheimer's disease: correlations with senile plaques and disease progression. J. Neuropathol. Exp. Neurol. 55:1134-42
202. Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, et al. 1998. A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am. J. Hum. Genet. 62:70-76
203. Upchurch M, Wehner JM. 1989. Inheritance of spatial learning ability in inbred mice: a classical genetic analysis. Behav. Neurosci. 103:1251-58
204. Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, et al. 1992. Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nat. Genet. 2:334-39
205. Van Broeckhoven C, Backhovens H, Cruts M, Martin JJ, Crook R, et al. 1994. APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neurosci. Lett. 169:179-80
206. Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, et al. 1990. Amyloid β protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 248:1120-22
207. Vogel G. 1998. Tau protein mutations confirmed as neuron killers. Science 280:1524-25
208. von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, et al. 1997. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18:661-69
209. Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD. 1997. Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations. Proc. Natl. Acad. Sci. USA 94:14900-5
210. Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, et al. 1992. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid-beta-protein precursor. Proc. Natl. Acad. Sci. USA 89:10758-62
211. Wasco W, Gurubhagavatula S, Paradis MD, Romano DM, Sisodia SS, et al. 1993. Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid β protein precursor. Nat. Genet. 5:95-99
212. Wavrant-DeVrieze F, Perez-Tur J, Lambert JC, Frigard B, Pasquier F, et al. 1997. Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease. Neurosci. Lett. 227:68-70
213. Webster S, Lue L-F, Brachova L, Tenner AJ, McGeer PL, et al. 1997. Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol. Aging 18:415-21
214. Weidemann A, König G, Bunke D, Fischer P, Salbaum JM, et al. 1989. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 57:115-26
215. Weisgraber KH, Pitas RE, Mahley RW. 1994. Lipoproteins, neurobiology, and Alzheimer's disease: structure and function of apolipoprotein E. Curr. Opin. Struct. Biol. 4:507-15
216. Weidemann A, Paliga K, Dirrwany U, Czech C, Erin G, et al. 1997. Formation of stable complexes between two Alzheimer's disease gene products: presenilin 2 and β-amyloid precursor protein. Nat. Med. 3:328-32
217. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, et al. 1982. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237-39
218. Wilhelmsen KC, Clark LN. 1998. Chromosome 17-linked dementias. See Ref. 113a, 9:170-80
219. Wisniewski T, Frangione B. 1992. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135:235-38
220. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJS, et al. 1997. Presenilin I is required for Notch1 and DIII expression in the paraxial mesoderm. Nature 387:288-92
221. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, et al. 1997. Amyloidogenic role of cytokine TGF-ß1 in transgenic mice and in Alzheimer's disease. Nature 389:603-6
222. Xia M, Qin S, McNamara M, Mackay C, Hyman BT. 1997. Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer's disease. Am. J. Pathol. 150:1267-74
223. Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. 1997. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94: 8208-13
224. Yankner BA. 1996. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16:921-32
225. Young AB, Penney JB Jr. 1994. Neurotransmitter receptors in Alzheimer disease. See Ref. 193a, pp. 293-303
226. Zheng H, Jiang M-H, Trumbauer ME, Sirinathsinghji DJS, Hopkins R, et al. 1995. β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525-31
227. Zhou J, Liyanage U, Medina M, Ho C, Simmons AD, et al. 1997. Presenilin 1 interaction in the brain with a novel member of the armadillo family. Neuroreport 8:2085-90