The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics

被引：1737

作者：

Karran, Eric ^{[1
]}

Mercken, Marc ^{[1
]}

De Strooper, Bart ^{[2
]}

机构：

[1] Janssen Res & Dev, Neurosci Therapeut Area, B-2340 Beerse, Belgium

[2] Katholieke Univ Leuven VIB, Dept Mol & Dev Genet, Louvain, Belgium

来源：

NATURE REVIEWS DRUG DISCOVERY | 2011年 / 10卷 / 09期

关键词：

GAMMA-SECRETASE INHIBITOR; GENOME-WIDE ASSOCIATION; CENTRAL-NERVOUS-SYSTEM; A-BETA; PRECURSOR PROTEIN; IN-VIVO; APOLIPOPROTEIN-E; MOUSE MODEL; PRESENILIN MUTATIONS; CLINICAL-TRIALS;

D O I：

10.1038/nrd3505

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

The amyloid cascade hypothesis, which posits that the deposition of the amyloid-beta peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-beta production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-beta-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.

引用

页码：698 / U1600

页数：15

共 149 条

[51] Long-Term In Vivo Imaging of β-Amyloid Plaque Appearance and Growth in a Mouse Model of Cerebral β-Amyloidosis [J].

Hefendehl, Jasmin K. ;

Wegenast-Braun, Bettina M. ;

Liebig, Christian ;

Eicke, Daniel ;

Milford, David ;

Calhoun, Michael E. ;

Kohsaka, Shinichi ;

Eichner, Martin ;

Jucker, Mathias .

JOURNAL OF NEUROSCIENCE, 2011, 31 (02) :624-629

[52] Comparison of Aβ levels in the brain of familial and sporadic Alzheimer's disease [J].

Hellstrom-Lindahl, E. ;

Viitanen, M. ;

Marutle, A. .

NEUROCHEMISTRY INTERNATIONAL, 2009, 55 (04) :243-252

[53] Survival in Alzheimer disease A multiethnic, population-based study of incident cases [J].

Helzner, E. P. ;

Scarmeas, N. ;

Cosentino, S. ;

Tang, M. X. ;

Schupf, N. ;

Stern, Y. .

NEUROLOGY, 2008, 71 (19) :1489-1495

[54] Solution state characterization of amyloid β-derived diffusible ligands [J].

Hepler, Robert W. ;

Grimm, Karen M. ;

Nahas, Deborah D. ;

Breese, Robert ;

Dodson, Elizabeth Chen ;

Acton, Paul ;

Keller, Paul M. ;

Yeager, Mark ;

Wang, Hui ;

Shughrue, Paul ;

Kinney, Gene ;

Joyce, Joseph G. .

BIOCHEMISTRY, 2006, 45 (51) :15157-15167

[55] Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency [J].

Herreman, A ;

Hartmann, D ;

Annaert, W ;

Saftig, P ;

Craessaerts, K ;

Serneels, L ;

Umans, L ;

Schrijvers, V ;

Checler, F ;

Vanderstichele, H ;

Baekelandt, V ;

Dressel, R ;

Cupers, P ;

Huylebroeck, D ;

Zwijsen, A ;

Van Leuven, F ;

De Strooper, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (21) :11872-11877

[56] Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease [J].

Hollingworth, Paul ;

Harold, Denise ;

Sims, Rebecca ;

Gerrish, Amy ;

Lambert, Jean-Charles ;

Carrasquillo, Minerva M. ;

Abraham, Richard ;

Hamshere, Marian L. ;

Pahwa, Jaspreet Singh ;

Moskvina, Valentina ;

Dowzell, Kimberley ;

Jones, Nicola ;

Stretton, Alexandra ;

Thomas, Charlene ;

Richards, Alex ;

Ivanov, Dobril ;

Widdowson, Caroline ;

Chapman, Jade ;

Lovestone, Simon ;

Powell, John ;

Proitsi, Petroula ;

Lupton, Michelle K. ;

Brayne, Carol ;

Rubinsztein, David C. ;

Gill, Michael ;

Lawlor, Brian ;

Lynch, Aoibhinn ;

Brown, Kristelle S. ;

Passmore, Peter A. ;

Craig, David ;

McGuinness, Bernadette ;

Todd, Stephen ;

Holmes, Clive ;

Mann, David ;

Smith, A. David ;

Beaumont, Helen ;

Warden, Donald ;

Wilcock, Gordon ;

Love, Seth ;

Kehoe, Patrick G. ;

Hooper, Nigel M. ;

Vardy, Emma R. L. C. ;

Hardy, John ;

Mead, Simon ;

Fox, Nick C. ;

Rossor, Martin ;

Collinge, John ;

Maier, Wolfgang ;

Jessen, Frank ;

Ruether, Eckart .

NATURE GENETICS, 2011, 43 (05) :429-+

[57] The clinical phenotype of familial and sporadic late onset Alzheimer's disease [J].

Holmes, C ;

Lovestone, S .

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, 2002, 17 (02) :146-149

[58] Genotype and phenotype in Alzheimer's disease [J].

Holmes, C .

BRITISH JOURNAL OF PSYCHIATRY, 2002, 180 :131-134

[59] Long-term effects of Aβ42 immunisation in Alzheimer's disease:: follow-up of a randomised, placebo-controlled phase I trial [J].

Holmes, Clive ;

Boche, Delphine ;

Wilkinson, David ;

Yadegarfar, Ghasem ;

Hopkins, Vivienne ;

Bayer, Anthony ;

Jones, Roy W. ;

Bullock, Roger ;

Love, Seth ;

Neal, James W. ;

Zotova, Elina ;

Nicoll, James A. R. .

LANCET, 2008, 372 (9634) :216-223

[60] Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease [J].

Holtzman, DM ;

Bales, KR ;

Tenkova, T ;

Fagan, AM ;

Parsadanian, M ;

Sartorius, LJ ;

Mackey, B ;

Olney, J ;

McKeel, D ;

Wozniak, D ;

Paul, SM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (06) :2892-2897

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