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Science 19 July 2002:
Vol. 297. no. 5580, pp. 353 - 356
DOI: 10.1126/science.1072994
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Review

The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

John Hardy,1 Dennis J. Selkoe2*

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta -peptide (Abeta ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.

1 Laboratories of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
2 Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: selkoe{at}cnd.bwh.harvard.edu

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F. Xu, M. P. Vitek, C. A. Colton, M. L. Previti, N. Gharkholonarehe, J. Davis, and W. E. Van Nostrand (2008)
J. Neurosci. 28, 5312-5320
   Abstract »    Full Text »    PDF »
Platinum-based inhibitors of amyloid-{beta} as therapeutic agents for Alzheimer's disease.
K. J. Barnham, V. B. Kenche, G. D. Ciccotosto, D. P. Smith, D. J. Tew, X. Liu, K. Perez, G. A. Cranston, T. J. Johanssen, I. Volitakis, et al. (2008)
PNAS 105, 6813-6818
   Abstract »    Full Text »    PDF »
Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis.
L. Haataja, T. Gurlo, C. J. Huang, and P. C. Butler (2008)
Endocr. Rev. 29, 303-316
   Abstract »    Full Text »    PDF »
Role of Insulin Metabolism Disturbances in the Development of Alzheimer Disease: Mini Review.
B. Sabayan, F. Foroughinia, A. Mowla, and A. Borhanihaghighi (2008)
American Journal of Alzheimer's Disease and Other Dementias 23, 192-199
   Abstract »    PDF »
Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits.
H. Belinson, D. Lev, E. Masliah, and D. M. Michaelson (2008)
J. Neurosci. 28, 4690-4701
   Abstract »    Full Text »    PDF »
Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance.
T. Bolmont, F. Haiss, D. Eicke, R. Radde, C. A. Mathis, W. E. Klunk, S. Kohsaka, M. Jucker, and M. E. Calhoun (2008)
J. Neurosci. 28, 4283-4292
   Abstract »    Full Text »    PDF »
{beta}-Amyloid1-42 Induces Neuronal Death through the p75 Neurotrophin Receptor.
A. Sotthibundhu, A. M. Sykes, B. Fox, C. K. Underwood, W. Thangnipon, and E. J. Coulson (2008)
J. Neurosci. 28, 3941-3946
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Stabilization of a {beta}-hairpin in monomeric Alzheimer's amyloid-{beta} peptide inhibits amyloid formation.
W. Hoyer, C. Gronwall, A. Jonsson, S. Stahl, and T. Hard (2008)
PNAS 105, 5099-5104
   Abstract »    Full Text »    PDF »
Characterization of Cullin-box Sequences That Direct Recruitment of Cul2-Rbx1 and Cul5-Rbx2 Modules to Elongin BC-based Ubiquitin Ligases.
N. Mahrour, W. B. Redwine, L. Florens, S. K. Swanson, S. Martin-Brown, W. D. Bradford, K. Staehling-Hampton, M. P. Washburn, R. C. Conaway, and J. W. Conaway (2008)
J. Biol. Chem. 283, 8005-8013
   Abstract »    Full Text »    PDF »
Lack of Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease after Overexpression of the Anti-Apoptotic Protein Bcl-2.
T. T. Rohn, V. Vyas, T. Hernandez-Estrada, K. E. Nichol, L.-A. Christie, and E. Head (2008)
J. Neurosci. 28, 3051-3059
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Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system.
M. Osterfield, R. Egelund, L. M. Young, and J. G. Flanagan (2008)
Development 135, 1189-1199
   Abstract »    Full Text »    PDF »
Retromer Sorting: A Pathogenic Pathway in Late-Onset Alzheimer Disease.
S. A. Small (2008)
Arch Neurol 65, 323-328
   Abstract »    Full Text »    PDF »
Genome-Wide Association Studies in Alzheimer Disease.
S. C. Waring and R. N. Rosenberg (2008)
Arch Neurol 65, 329-334
   Abstract »    Full Text »    PDF »
In Vivo {beta}-Secretase 1 Inhibition Leads to Brain A{beta} Lowering and Increased {alpha}-Secretase Processing of Amyloid Precursor Protein without Effect on Neuregulin-1.
S. Sankaranarayanan, E. A. Price, G. Wu, M.-C. Crouthamel, X.-P. Shi, K. Tugusheva, K. X. Tyler, J. Kahana, J. Ellis, L. Jin, et al. (2008)
J. Pharmacol. Exp. Ther. 324, 957-969
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Progression of Amyloid Pathology to Alzheimer's Disease Pathology in an Amyloid Precursor Protein Transgenic Mouse Model by Removal of Nitric Oxide Synthase 2.
D. M. Wilcock, M. R. Lewis, W. E. Van Nostrand, J. Davis, M. L. Previti, N. Gharkholonarehe, M. P. Vitek, and C. A. Colton (2008)
J. Neurosci. 28, 1537-1545
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