Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies
Authors: Dennis J. Selkoe
Journal: Annals of Internal Medicine (2004)

Reviews20 April 2004Alzheimer Disease: Mechanistic Understanding Predicts Novel TherapiesDennis J. Selkoe, MDDennis J. Selkoe, MDFrom Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-140-8-200404200-00047 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical PrinciplesAlzheimer disease usually begins with gradual failure of recent memory with preserved alertness and motor function.The syndrome of minimal cognitive impairment (mild cognitive impairment)—a subtle decrease in short-term declarative memory with otherwise normal cognition—is often a harbinger of Alzheimer disease.Alzheimer disease progresses slowly to involve many cognitive spheres and shortens life expectancy, with most patients ultimately dying of secondary respiratory complications (for example, aspiration and pneumonia).Treatment with acetylcholinesterase inhibitors can temporarily alleviate some symptoms but does not modify disease progression.A noncompetitive N-methyl-d-aspartate–receptor antagonist (memantine) has recently been approved as a noncholinergic symptomatic treatment.Epidemiologic data suggest that long-term use of ...References1. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885-90. [PMID: 6375662] CrossrefMedlineGoogle Scholar2. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al . The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325:733-6. [PMID: 2881207] CrossrefMedlineGoogle Scholar3. Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Harigaya Y. Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol (Berl). 1988;77:113-9. [PMID: 2465658] MedlineGoogle Scholar4. Tagliavini F, Giaccone G, Frangione B, Bugiani O. Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals. Neurosci Lett. 1988;93:191-6. [PMID: 3241644] CrossrefMedlineGoogle Scholar5. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45-53. [PMID: 8043280] CrossrefMedlineGoogle Scholar6. Cummings BJ, Pike CJ, Shankle R, Cotman CW. Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiol Aging. 1996;17:921-33. [PMID: 9363804] CrossrefMedlineGoogle Scholar7. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al . Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283:1571-7. [PMID: 10735393] CrossrefMedlineGoogle Scholar8. Verbeek MM, de Waal RM, Vinters HV. Cerebral Amyloid Angiopathy in Alzheimer's Disease and Related Disorders. Dordrecht, the Netherlands: Kluwer Academic; 2000:357. Google Scholar9. Goedert M, Spillantini MG. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. Biochim Biophys Acta. 2000;1502:110-21. [PMID: 10899436] CrossrefMedlineGoogle Scholar10. Kondo J, Honda T, Mori H, Hamada Y, Miura R, Ogawara M, et al . The carboxyl third of tau is tightly bound to paired helical filaments. Neuron. 1988;1:827-34. [PMID: 2483105] CrossrefMedlineGoogle Scholar11. Lee VM, Balin BJ, Otvos L, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991;251:675-8. [PMID: 1899488] CrossrefMedlineGoogle Scholar12. Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122:1131-5. [PMID: 6236805] CrossrefMedlineGoogle Scholar13. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741-66. [PMID: 11274343] CrossrefMedlineGoogle Scholar14. Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, et al . beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995;81:525-31. [PMID: 7758106] CrossrefMedlineGoogle Scholar15. Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci U S A. 1992;89:10758-62. [PMID: 1279693] CrossrefMedlineGoogle Scholar16. Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem. 1994;269:2637-44. [PMID: 8300594] CrossrefMedlineGoogle Scholar17. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al . Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322-5. [PMID: 1383826] CrossrefMedlineGoogle Scholar18. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, et al . Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258:126-9. [PMID: 1439760] CrossrefMedlineGoogle Scholar19. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, et al . Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature. 1992;359:325-7. [PMID: 1406936] CrossrefMedlineGoogle Scholar20. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al . Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735-41. [PMID: 10531052] CrossrefMedlineGoogle Scholar21. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, et al . Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999;402:537-40. [PMID: 10591214] CrossrefMedlineGoogle Scholar22. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, et al . Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999;402:533-7. [PMID: 10591213] CrossrefMedlineGoogle Scholar23. Cao X, Sudhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001;293:115-20. [PMID: 11441186] CrossrefMedlineGoogle Scholar24. Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. 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. 2001;276:40288-92. [PMID: 11544248] CrossrefMedlineGoogle Scholar25. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, et al . Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2001;2:835-41. [PMID: 11520861] CrossrefMedlineGoogle Scholar26. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al . Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977-81. [PMID: 8446617] CrossrefMedlineGoogle Scholar27. Selkoe DJ. The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins. Neurol Clin. 2000;18:903-22. [PMID: 11072267] CrossrefMedlineGoogle Scholar28. Price DL, Wong PC, Markowska AL, Lee MK, Thinakaren G, Cleveland DW, et al . The value of transgenic models for the study of neurodegenerative diseases. Ann N Y Acad Sci. 2000;920:179-91. [PMID: 11193148] CrossrefMedlineGoogle Scholar29. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al . Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467-72. [PMID: 8350998] CrossrefMedlineGoogle Scholar30. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754-60. [PMID: 7596406] CrossrefMedlineGoogle Scholar31. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al . Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269:973-7. [PMID: 7638622] CrossrefMedlineGoogle Scholar32. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775-8. [PMID: 7651536] CrossrefMedlineGoogle Scholar33. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95:7737-41. [PMID: 9636220] CrossrefMedlineGoogle Scholar34. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702-5. [PMID: 9641683] CrossrefMedlineGoogle Scholar35. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, et al . Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998;282:1914-7. [PMID: 9836646] CrossrefMedlineGoogle Scholar36. Goedert M, Crowther RA, Spillantini MG. Tau mutations cause frontotemporal dementias. Neuron. 1998;21:955-8. [PMID: 9856453] CrossrefMedlineGoogle Scholar37. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996;3:16-32. [PMID: 9173910] CrossrefMedlineGoogle Scholar38. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al . Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248:1124-6. [PMID: 2111584] CrossrefMedlineGoogle Scholar39. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, et al . Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:9649-53. [PMID: 8415756] CrossrefMedlineGoogle Scholar40. Ma J, Yee A, Brewer HB, Das S, Potter H. Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature. 1994;372:92-4. [PMID: 7969426] CrossrefMedlineGoogle Scholar41. Evans KC, Berger EP, Cho CG, Weisgraber KH, Lansbury PT. 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 U S A. 1995;92:763-7. [PMID: 7846048] CrossrefMedlineGoogle Scholar42. Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, et al . Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 1999;96:15233-8. [PMID: 10611368] CrossrefMedlineGoogle Scholar43. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, et al . Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000;97:2892-7. [PMID: 10694577] CrossrefMedlineGoogle Scholar44. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al . Secreted amyloid beta-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. 1996;2:864-70. [PMID: 8705854] CrossrefMedlineGoogle Scholar45. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, et al . Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998;4:97-100. [PMID: 9427614] CrossrefMedlineGoogle Scholar46. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, et al . The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996;2:1146-50. [PMID: 8837617] CrossrefMedlineGoogle Scholar47. Mann DM, Iwatsubo T, Cairns NJ, Lantos PL, Nochlin D, Sumi SM, et al . Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer's disease: predominance of Abeta42(43). Ann Neurol. 1996;40:149-56. [PMID: 8773595] CrossrefMedlineGoogle Scholar48. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, et al . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996;17:181-90. [PMID: 8755489] CrossrefMedlineGoogle Scholar49. Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995;377:351-4. [PMID: 7566091] CrossrefMedlineGoogle Scholar50. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al . A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518-22. [PMID: 10206645] CrossrefMedlineGoogle Scholar51. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629-39. [PMID: 9160754] CrossrefMedlineGoogle Scholar52. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al . Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387-90. [PMID: 9450754] CrossrefMedlineGoogle Scholar53. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398:513-7. [PMID: 10206644] CrossrefMedlineGoogle Scholar54. Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc Natl Acad Sci U S A. 1997;94:8208-13. [PMID: 9223340] CrossrefMedlineGoogle Scholar55. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Rahmati T, et al . Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry. 1999;38:4720-7. [PMID: 10200159] CrossrefMedlineGoogle Scholar56. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, et al . Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol. 2000;2:428-34. [PMID: 10878808] CrossrefMedlineGoogle Scholar57. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, et al . Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689-94. [PMID: 10864326] CrossrefMedlineGoogle Scholar58. Berezovska O, Jack C, Deng A, Gastineau N, Rebeck GW, Hyman BT. Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage. J Biol Chem. 2001;276:30018-23. [PMID: 11408475] CrossrefMedlineGoogle Scholar59. Skovronsky DM, Doms RW, Lee VM. Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol. 1998;141:1031-9. [PMID: 9585420] CrossrefMedlineGoogle Scholar60. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ. The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry. 2000;39:10831-9. [PMID: 10978169] CrossrefMedlineGoogle Scholar61. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998;95:6448-53. [PMID: 9600986] CrossrefMedlineGoogle Scholar62. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al . Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535-9. [PMID: 11932745] CrossrefMedlineGoogle Scholar63. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al . Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21:383-421. [PMID: 10858586] CrossrefMedlineGoogle Scholar64. Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77:817-27. [PMID: 8004671] CrossrefMedlineGoogle Scholar65. Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM. Direct evidence of oxidative injury produced by the Alzheimer's beta-amyloid peptide (1-40) in cultured hippocampal neurons. Exp Neurol. 1995;131:193-202. [PMID: 7895820] CrossrefMedlineGoogle Scholar66. Markesbery WR. The role of oxidative stress in Alzheimer disease. Arch Neurol. 1999;56:1449-52. [PMID: 10593298] CrossrefMedlineGoogle Scholar67. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al . A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336:1216-22. [PMID: 9110909] CrossrefMedlineGoogle Scholar68. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992;12:376-89. [PMID: 1346802] CrossrefMedlineGoogle Scholar69. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci. 1993;13:1676-87. [PMID: 8463843] CrossrefMedlineGoogle Scholar70. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A. 1994;91:12243-7. [PMID: 7991613] CrossrefMedlineGoogle Scholar71. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999;402:615-22. [PMID: 10604467] CrossrefMedlineGoogle Scholar72. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al . Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293:1487-91. [PMID: 11520987] CrossrefMedlineGoogle Scholar73. Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med. 1999;341:1670-9. [PMID: 10572156] CrossrefMedlineGoogle Scholar74. Zajaczkowski W, Hetman M, Nikolaev E, Quack G, Danysz W, Kaczmarek L. Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists. Neurotox Res. 2000;1:299-310. [PMID: 12835097] CrossrefMedlineGoogle Scholar75. Jain KK. Evaluation of memantine for neuroprotection in dementia. Expert Opin Investig Drugs. 2000;9:1397-406. [PMID: 11060751] CrossrefMedlineGoogle Scholar76. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303-8. [PMID: 10190820] CrossrefMedlineGoogle Scholar77. Morris JC, Storandt M, McKeel DW, Rubin EH, Price JL, Grant EA, et al . Cerebral amyloid deposition and diffuse plaques in "normal" aging: Evidence for presymptomatic and very mild Alzheimer's disease. Neurology. 1996;46:707-19. [PMID: 8618671] CrossrefMedlineGoogle Scholar78. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A. 2003;100:6382-7. [PMID: 12740439] CrossrefMedlineGoogle Scholar79. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al . Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000;290:150-3. [PMID: 11021803] CrossrefMedlineGoogle Scholar80. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al . BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci. 2001;4:233-4. [PMID: 11224536] CrossrefMedlineGoogle Scholar81. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al . Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173-7. [PMID: 10408445] CrossrefMedlineGoogle Scholar82. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al . A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000;408:979-82. [PMID: 11140685] CrossrefMedlineGoogle Scholar83. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al . A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000;408:982-5. [PMID: 11140686] CrossrefMedlineGoogle Scholar84. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, et al . Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. 2000;48:567-79. [PMID: 11026440] CrossrefMedlineGoogle Scholar85. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al . Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916-9. [PMID: 10932230] CrossrefMedlineGoogle Scholar86. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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 U S A. 2001;98:8850-5. [PMID: 11438712] CrossrefMedlineGoogle Scholar87. Selkoe DJ, Shankar GM, Fadeeva JV, Walsh DM. Modulation and further characterization of natural, cell-derived Aβ oligomers [Abstract]. Annual Meeting of the Society for Neuroscience, New Orleans, LA, 8-12 November 2003. Abstract no. 667.7. Available at www.sfn.org. Google Scholar88. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2003;43:545-84. [PMID: 12415125] CrossrefMedlineGoogle Scholar89. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, et al . Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003;38:547-54. [PMID: 12765607] CrossrefMedlineGoogle Scholar90. in t'. Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T. et al , Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001;345:1515-21. [PMID: 11794217] CrossrefMedlineGoogle Scholar91. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al . A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414:212-6. [PMID: 11700559] CrossrefMedlineGoogle Scholar92. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al . Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001;30:665-76. [PMID: 11430801] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.For definition of terms used, see Glossary.Acknowledgments: The author thanks his colleagues and collaborators for many helpful discussions.Grant Support: By the National Institutes of Health, Alzheimer's Association, and the Foundation for Neurologic Diseases. Dr. Selkoe is a founding scientist of Athena Neurosciences, now Elan Corporation.Disclosures:Honoraria and Patents received: Elan Corp.Corresponding Author: Dennis J. Selkoe, MD, Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115. 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degeneration via JNK3Aptamers Selected for Recognizing Amyloid β-Protein—A Case for Cautious OptimismDissecting Endoplasmic Reticulum Unfolded Protein Response (UPRER) in Managing Clandestine Modus Operandi of Alzheimer's DiseaseDisaggregation of Aβ42 for Structural and Biochemical StudiesThe influence of GAPT extraction on synapse loss of APPswe/PS1dE9 transgenic mice via adjusting Bcl‐2/Bax balanceβ-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic ProcessingiPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer's DiseaseFilling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processingLimited activation of the intrinsic apoptotic pathway plays a main role in amyloid-β-induced apoptosis without eliciting the activation of the extrinsic apoptotic pathwaySynthesis and biological evaluation of curcumin analogs as β-amyloid imaging agentsA novel monoclonal antibody against the N-terminus of Aβ1-42 reduces plaques and improves cognition in a mouse model of Alzheimer's diseaseSelf-Assembly and Anti-Amyloid Cytotoxicity Activity of Amyloid beta Peptide DerivativesAssociation between injury severity and amyloid β protein levels in serum and cerebrospinal fluid in rats with traumatic spinal cord injuryVascular dysfunction-associated with Alzheimer's diseaseEffects of altered RTN3 expression on BACE1 activity and Alzheimer's neuritic pl