Amyloid-β in Alzheimer disease: The null versus the alternate hypotheses

Journal of Pharmacology and Experimental Therapeutics

Volumn 321, Issue 3, 2007, Pages 823-829

  Lee, Hyoung Gon ^a   Zhu, Xiongwei ^a   Castellani, Rudy J ^b   Nunomura, Akihiko ^c   Perry, George ^a,d   Smith, Mark A ^a  

^a CASE WESTERN RESERVE UNIVERSITY   (United States)

^b UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^c ASAHIKAWA MEDICAL COLLEGE   (Japan)

^d University of San Antonio   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; GAMMA SECRETASE; PRESENILIN 1; REACTIVE OXYGEN METABOLITE; SCAVENGER;

ALZHEIMER DISEASE; CHROMOSOME 1; CHROMOSOME 14; FAMILIAL DISEASE; GENE MUTATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NEUROTOXICITY; NONHUMAN; NULL HYPOTHESIS; OXIDATIVE STRESS; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN METABOLISM; REVIEW;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; ANIMALS; APOLIPOPROTEIN E4; HUMANS; NEURONS; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES;

EID: 34248560960     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.106.114009     Document Type: Review

References (130)

1. Akama KT, Albanese C, Pestell RG, and Van Eldik LJ (1998) Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism. Proc Natl Acad Sci USA 95:5795-5800.
2. Andorn AC and Kalaria RN (2000) Factors affecting pro- and anti-oxidant properties of fragments of the b-protein precursor (bPP): implication for Alzheimer's disease. J Alzheimers Dis 2:69-78.
3. Atwood CS, Huang X, Moir RD, Smith MA, Tanzi RE, Roher AE, Bush AI, and Perry G (2001) Neuroinflammatory responses in the Alzheimer's disease brain promote the oxidative post-translation modification of amyloid deposits., in Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics (Iqbal K, Sisodia SS and Winblad B eds) pp 341-361, John Wiley & Sons, Ltd., Chichester, UK.
4. Atwood CS, Martins RN, Smith MA, and Perry G (2002) Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins. Peptides 23:1343-1350.
5. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, and Bush AI (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273:12817-12826.
6. Behl C, Davis J, Cole GM, and Schubert D (1992) Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun 186:944-950.
7. Bishop GM and Robinson SR (2003) Human Abeta1 - 42 reduces iron-induced toxicity in rat cerebral cortex. J Neurosci Res 73:316-323.
8. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, and McLean AJ (1995) Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12:565-572.
9. Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, and Mariani J (1995) Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci USA 92:3032-3035.
10. 2+, nitroxide spin probes, and synaptosomal membrane proteins. Life Sci 58:217-228.
11. Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, and Black RA (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273:27765-27767.
12. Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, and Greengard P (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci USA 89:10075-10078.
13. Cai XD, Golde TE, and Younkin SG (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259:514-516.
14. Canning DR, McKeon RJ, DeWitt DA, Perry G, Wujek JR, Frederickson RC, and Silver J (1993) beta-Amyloid of Alzheimer's disease induces reactive gliosis that inhibits axonal outgrowth. Exp Neurol 124:289-298.
15. Carpenter MK, Crutcher KA, and Kater SB (1993) An analysis of the effects of Alzheimer's plaques on living neurons. Neurobiol Aging 14:207-215.
16. Ciallella JR, Rangnekar VV, and McGillis JP (1994) Heat shock alters Alzheimer's beta amyloid precursor protein expression in human endothelial cells. J Neurosci Res 37:769-776.
17. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, and Selkoe DJ (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360:672-674.
18. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, et al. (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67-72.
19. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7:180-184.
20. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, and Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923.
21. Cotman CW, Pike CJ, and Copani A (1992) beta-Amyloid neurotoxicity: a discussion of in vitro findings. Neurobiol Aging 13:587-590.
22. Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, and Wolfson L (1988) Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 38:1682-1687.
23. Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT, Atwood CS, Huang X, Farrag YW, Perry G, and Bush AI (2000) Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275:19439-19442.
24. Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, and Masters CL (1988) A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688-1693.
25. Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, et al. (2002) Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci 22:3445-3453.
26. DeWitt DA, Perry G, Cohen M, Doller C, and Silver J (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp Neurol 149:329-340.
27. Dikalov SI, Vitek MP, Maples KR, and Mason RP (1999) Amyloid beta peptides do not form peptide-derived free radicals spontaneously, but can enhance metalcatalyzed oxidation of hydroxylamines to nitroxides. J Biol Chem 274:9392-9399.
28. Figueroa DJ, Shi XP, Gardell SJ, and Austin CP (2001) Abetapp secretases are co-expressed with Abetapp in the pancreatic islets. J Alzheimers Dis 3:393-396.
29. Frederikse PH, Garland D, Zigler JS Jr, and Piatigorsky J (1996) Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem 271:10169-10174.
30. Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B, and Groswasser Z (1999) Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 52:244-248.
31. Gabuzda D, Busciglio J, Chen LB, Matsudaira P, and Yankner BA (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269:13623-13628.
32. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, et al. (2006) Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci USA 103:7130-7135.
33. Geddes JF, Vowles GH, Beer TW, and Ellison DW (1997) The diagnosis of diffuse axonal injury: implications for forensic practice. Neuropathol Appl Neurobiol 23: 339-347.
34. Geddes JW, Anderson KJ, and Cotman CW (1986) Senile plaques as aberrant sprout-stimulating structures. Exp Neurol 94:767-776.
35. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, and Roberts GW (1993) Betaamyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 160:139-144.
36. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, and Hof PR (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60:1495-1500.
37. Glenner GG and Wong CW (1984a) Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122:1131-1135.
38. Glenner GG and Wong CW (1984b) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885-890.
39. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704-706.
40. Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, Vitek MP, and Gajdusek DC (1989) Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci USA 86:7606-7610.
41. Gooch MD and Stennett DJ (1996) Molecular basis of Alzheimer's disease. Am J Health Syst Pharm 53:1544-1603.
42. Greenberg BD, Savage MJ, Howland DS, Ali SM, Siedlak SL, Perry G, Siman R, and Scott RW (1996) APP transgenesis: approaches toward the development of animal models for Alzheimer disease neuropathology. Neurobiol Aging 17:153-171.
43. Guillozet AL, Weintraub S, Mash DC, and Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729-736.
44. Haass C and Steiner H (2002) Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol 12:556-562.
45. Hall ED, Oostveen JA, Dunn E, and Carter DB (1995) Increased amyloid protein precursor and apolipoprotein E immunoreactivity in the selectively vulnerable hippocampus following transient forebrain ischemia in gerbils. Exp Neurol 135: 17-27.
46. Hardy J (2006) Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimers Dis 9:151-153.
47. Hardy JA and Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256:184-185.
48. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, and Butterfield DA (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270-3274.
49. Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, and Van Leuven F (2003) Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem 278:2484-2489.
50. Higgins GA, Oyler GA, Neve RL, Chen KS, and Gage FH (1990) Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats. Proc Natl Acad Sci USA 87:3032-3036.
51. Holscher C (1998) Possible causes of Alzheimer's disease: amyloid fragments, free radicals, and calcium homeostasis. Neurobiol Dis 5:129-141.
52. Horsburgh K, McCarron MO, White F, and Nicoll JA (2000) The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models. Neurobiol Aging 21:245-255.
53. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, and Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99-102.
54. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, et al. (1999a) The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38:7609-7616.
55. Huang X, Atwood CS, Moir RD, Hartshorn MA, Vonsattel JP, Tanzi RE, and Bush AI (1997) Zinc-induced Alzheimer's Abeta1-40 aggregation is mediated by conformational factors. J Biol Chem 272:26464-26470.
56. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, et al. (1999b) Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274:37111-37116.
57. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, and Hyman BT (1997a) APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965-973.
58. Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, and Hyman BT (1997b) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053-7059.
59. Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, and Gordon MN (2002) Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci 22: 2246-2254.
60. Jendroska K, Poewe W, Daniel SE, Pluess J, Iwerssen-Schmidt H, Paulsen J, Barthel S, Schelosky L, Cervos-Navarro J, and DeArmond SJ (1995) Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol (Berl) 90:461-466.
61. Josefson D (2002) Doctors successfully screen embryos for gene mutation linked to early onset Alzheimer's. BMJ 324:564.
62. Kawai M, Cras P, and Perry G (1992) Serial reconstruction of beta-protein amyloid plaques: relationship to microvessels and size distribution. Brain Res 592:278-282.
63. Kontush A, Berndt C, Weber W, Akopyan V, Arlt S, Schippling S, and Beisiegel U (2001) Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic Biol Med 30:119-128.
64. Koo EH, Park L, and Selkoe DJ (1993) Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. Proc Natl Acad Sci USA 90:4748-4752.
65. Kowall NW, McKee AC, Yankner BA, and Beal MF (1992) In vivo neurotoxicity of beta-amyloid [beta(1-40)] and the beta(25-35) fragment. Neurobiol Aging 13:537-542.
66. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, and Jay G (1995) The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 9:21-30.
67. Lee HG, Casadesus G, Zhu X, Joseph JA, Perry G, and Smith MA (2004a) Perspectives on the amyloid-beta cascade hypothesis. J Alzheimers Dis 6:137-145.
68. Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, and Smith MA (2004b) Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann NY Acad Sci 1019:1-4.
69. Lee HG, Petersen RB, Zhu X, Honda K, Aliev G, Smith MA, and Perry G (2003) Will preventing protein aggregates live up to its promise as prophylaxis against neurodegenerative diseases? Brain Pathol 13:630-638.
70. Lee HG, Zhu X, Nunomura A, Perry G, and Smith MA (2006) Amyloid beta: the alternate hypothesis. Curr Alzheimer Res 3:75-80.
71. Lendon CL, Ashall F, and Goate AM (1997) Exploring the etiology of Alzheimer disease using molecular genetics. JAMA 277:825-831.
72. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, and Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352-357.
73. Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, et al. (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 20:5709-5714.
74. Ling X, Martins RN, Racchi M, Craft S, and Helmerhorst E (2002) Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor. J Alzheimers Dis 4:369-374.
75. Lleo A, Berezovska O, Growdon JH, and Hyman BT (2004) Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 12:146-156.
76. Lorenzo A and Yankner BA (1996) Amyloid fibril toxicity in Alzheimer's disease and diabetes. Ann NY Acad Sci 777:89-95.
77. Luo Y, Sunderland T, Roth GS, and Wolozin B (1996) Physiological levels of betaamyloid peptide promote PC12 cell proliferation. Neurosci Lett 217:125-128.
78. Mann DM, Jones D, South PW, Snowden JS, and Neary D (1992) Deposition of amyloid beta protein in non-Alzheimer dementias: evidence for a neuronal origin of parenchymal deposits of beta protein in neurodegenerative disease. Acta Neuropathol (Berl) 83:415-419.
79. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, and Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245-4249.
80. Mattson MP (1995) Degenerative and protective signaling mechanisms in the neurofibrillary pathology of AD. Neurobiol Aging 16:447-463.
81. Mattson MP and Pedersen WA (1998) Effects of amyloid precursor protein derivatives and oxidative stress on basal forebrain cholinergic systems in Alzheimer's disease. Int J Dev Neurosci 16:737-753.
82. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, and Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647-650.
83. Murakami N, Yamaki T, Iwamoto Y, Sakakibara T, Kobori N, Fushiki S, and Ueda S (1998) Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus. J Neurotrauma 15:993-1003.
84. Neve RL and Robakis NK (1998) Alzheimer's disease: a re-examination of the amyloid hypothesis. Trends Neurosci 21:15-19.
85. Nordstedt C, Gandy SE, Alafuzoff I, Caporaso GL, Iverfeldt K, Grebb JA, Winblad B, and Greengard P (1991) Alzheimer beta/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment. Proc Natl Acad Sci USA 88:8910-8914.
86. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759-767.
87. Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, and Smith MA (2000) Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011-1017.
88. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, and Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci 19:1959-1964.
89. Panegyres PK (1998) The effects of excitotoxicity on the expression of the amyloid precursor protein gene in the brain and its modulation by neuroprotective agents. J Neural Transm 105:463-478.
90. Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, Zaccheo D, Odetti P, Strocchi P, Marinari UM, et al. (2000) Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 268:642-646.
91. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, and Cotman CW (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 13:1676-1687.
92. Pike CJ, Walencewicz AJ, Glabe CG, and Cotman CW (1991) Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. Eur J Pharmacol 207:367-368.
93. Poirier J, Baccichet A, Dea D, and Gauthier S (1993) Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience 55:81-90.
94. Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, and Smith MA (2001) Abortive apoptosis in Alzheimer's disease. Acta Neuropathol (Berl) 101:305-310.
95. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, and Graham DI (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 57: 419-425.
96. Rogers J and Morrison JH (1985) Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer's disease. J Neurosci 5:2801-2808.
97. Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, Perry G, and Smith MA (2001) Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med 30:447-450.
98. Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, Gouras GK, Kirkwood A, Morris RG, and Shen J (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25:6755-6764.
99. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, and Smith MA (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. J Neurochem 74:270-279.
100. Sayre LM, Zagorski MG, Surewicz WK, Krafft GA, and Perry G (1997) Mechanisms of neurotoxicity associated with amyloid beta deposition and the role of free radicals in the pathogenesis of Alzheimer's disease: a critical appraisal. Chem Res Toxicol 10:518-526.
101. Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, and Smith MA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 68:2092-2097.
102. Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, and Markesbery WR (2000) "Preclinical" AD revisited: neuropathology of cognitively normal older adults. Neurology 55:370-376.
103. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature (Lond) 399:A23-A31.
104. Shi J, Xiang Y, and Simpkins JW (1997) Hypoglycemia enhances the expression of mRNA encoding beta-amyloid precursor protein in rat primary cortical astroglial cells. Brain Res 772:247-251.
105. Singh VK, Cheng JF, and Leu SJ (1994) Effect of substance P and protein kinase inhibitors on beta-amyloid peptide-induced proliferation of cultured brain cells. Brain Res 660:353-356.
106. Smith MA, Casadesus G, Joseph JA, and Perry G (2002) Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med 33:1194-1199.
107. Smith MA, Harris PL, Sayre LM, and Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866-9868.
108. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, and Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212-2215.
109. Smith MA, Richey PL, Taneda S, Kutty RK, Sayre LM, Monnier VM, and Perry G (1994) Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer's disease. Ann NY Acad Sci 738:447-454.
110. Sorbi S, Nacmias B, Piacentini S, Repice A, Latorraca S, Forleo P, and Amaducci L (1995) ApoE as a prognostic factor for post-traumatic coma. Nat Med 1:852.
111. Suzuki T, Oishi M, Marshak DR, Czernik AJ, Nairn AC, and Greengard P (1994) Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J 13:1114-1122.
112. Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, Capell A, Walter J, Grunberg J, Haass C, et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sci USA 94:2025-2030.
113. Topper R, Gehrmann J, Banati R, Schwarz M, Block F, Noth J, and Kreutzberg GW (1995) Rapid appearance of beta-amyloid precursor protein immunoreactivity in glial cells following excitotoxic brain injury. Acta Neuropathol (Berl) 89:23-28.
114. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, and Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126: 981-993.
115. Turnbull S, Tabner BJ, El-Agnaf OM, Twyman LJ, and Allsop D (2001) New evidence that the Alzheimer beta-amyloid peptide does not spontaneously form free radicals: an ESR study using a series of spin-traps. Free Radic Biol Med 30:1154-1162.
116. van Gool WA, Schenk DB, and Bolhuis PA (1994) Concentrations of amyloid-beta protein in cerebrospinal fluid increase with age in patients free from neurodegenerative disease. Neurosci Lett 172:122-124.
117. Van Muiswinkel FL, Veerhuis R, and Eikelenboom P (1996) Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 66:2468-2476.
118. Wallace W, Ahlers ST, Gotlib J, Bragin V, Sugar J, Gluck R, Shea PA, Davis KL, and Haroutunian V (1993) Amyloid precursor protein in the cerebral cortex is rapidly and persistently induced by loss of subcortical innervation. Proc Natl Acad Sci USA 90:8712-8716.
119. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, et al. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212-216.
120. Whitson JS, Glabe CG, Shintani E, Abcar A, and Cotman CW (1990) Beta-amyloid protein promotes neuritic branching in hippocampal cultures. Neurosci Lett 110: 319-324.
121. Whitson JS, Selkoe DJ, and Cotman CW (1989) Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490.
122. Wisniewski T, Castano EM, Golabek A, Vogel T, and Frangione B (1994) Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. Am J Pathol 145:1030-1035.
123. Xiong Y, Gu Q, Peterson PL, Muizelaar JP, and Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23-34.
124. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, and Smith MA (1994) Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91:7787-7791.
125. Yankner BA (1996) New clues to Alzheimer's disease: unraveling the roles of amyloid and tau. Nat Med 2:850-852.
126. Yankner BA, Duffy LK, and Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279-282.
127. Yokota M, Saido TC, Tani E, Yamaura I, and Minami N (1996) Cytotoxic fragment of amyloid precursor protein accumulates in hippocampus after global forebrain ischemia. J Cereb Blood Flow Metab 16:1219-1223.
128. Zheng H, Xu H, Uljon SN, Gross R, Hardy K, Gaynor J, Lafrancois J, Simpkins J, Refolo LM, Petanceska S, et al. (2002) Modulation of A(beta) peptides by estrogen in mouse models. J Neurochem 80:191-196.
129. Zhu X, Lee HG, Casadesus G, Avila J, Drew K, Perry G, and Smith MA (2005) Oxidative imbalance in Alzheimer's disease. Mol Neurobiol 31:205-217.
130. Zou K, Gong JS, Yanagisawa K, and Michikawa M (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 22:4833-4841.