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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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Intramembrane Proteolysis by {gamma}-Secretase.
H. Steiner, R. Fluhrer, and C. Haass (2008)
J. Biol. Chem. 283, 29627-29631
   Abstract »    Full Text »    PDF »
Structural Classification of Toxic Amyloid Oligomers.
C. G. Glabe (2008)
J. Biol. Chem. 283, 29639-29643
   Abstract »    Full Text »    PDF »
Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats.
C. K. Jones, A. E. Brady, A. A. Davis, Z. Xiang, M. Bubser, M. N. Tantawy, A. S. Kane, T. M. Bridges, J. P. Kennedy, S. R. Bradley, et al. (2008)
J. Neurosci. 28, 10422-10433
   Abstract »    Full Text »    PDF »
Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and A{beta} Pathology in a Transgenic Mouse Model of Alzheimer's Disease.
H. Onozuka, A. Nakajima, K. Matsuzaki, R.-W. Shin, K. Ogino, D. Saigusa, N. Tetsu, A. Yokosuka, Y. Sashida, Y. Mimaki, et al. (2008)
J. Pharmacol. Exp. Ther. 326, 739-744
   Abstract »    Full Text »    PDF »
BACE1 Knock-Outs Display Deficits in Activity-Dependent Potentiation of Synaptic Transmission at Mossy Fiber to CA3 Synapses in the Hippocampus.
H. Wang, L. Song, F. Laird, P. C. Wong, and H.-K. Lee (2008)
J. Neurosci. 28, 8677-8681
   Abstract »    Full Text »    PDF »
Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?.
S. Daumas, J. Sandin, K. S. Chen, D. Kobayashi, J. Tulloch, S. J. Martin, D. Games, and R. G.M. Morris (2008)
Learn. Mem. 15, 625-632
   Abstract »    Full Text »    PDF »
The Amyloid-{beta} Rise and {gamma}-Secretase Inhibitor Potency Depend on the Level of Substrate Expression.
C. R. Burton, J. E. Meredith, D. M. Barten, M. E. Goldstein, C. M. Krause, C. J. Kieras, L. Sisk, L. G. Iben, C. Polson, M. W. Thompson, et al. (2008)
J. Biol. Chem. 283, 22992-23003
   Abstract »    Full Text »    PDF »
Presenilins: Members of the {gamma}-Secretase Quartets, But Part-Time Soloists Too.
T. Wakabayashi and B. De Strooper (2008)
Physiology 23, 194-204
   Abstract »    Full Text »    PDF »
Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.
D. Han-Xiang, J. Hujun, F. Ronggen, Z. Hong, S. Yong, L. Erdong, H. Makito, C. D. C. Mauro, and S. Teepu (2008)
Hum. Mol. Genet. 17, 2310-2319
   Abstract »    Full Text »    PDF »
Glu332 in the Nicastrin Ectodomain Is Essential for {gamma}-Secretase Complex Maturation but Not for Its Activity.
L. Chavez-Gutierrez, A. Tolia, E. Maes, T. Li, P. C. Wong, and B. de Strooper (2008)
J. Biol. Chem. 283, 20096-20105
   Abstract »    Full Text »    PDF »
Abeta Predictor of Alzheimer Disease Symptoms.
C. F. Sephton and G. Yu (2008)
Arch Neurol 65, 875-876
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Distinct Pools of {beta}-Amyloid in Alzheimer Disease-Affected Brain: A Clinicopathologic Study.
J. R. Steinerman, M. Irizarry, N. Scarmeas, S. Raju, J. Brandt, M. Albert, D. Blacker, B. Hyman, and Y. Stern (2008)
Arch Neurol 65, 906-912
   Abstract »    Full Text »    PDF »
Grape-Derived Polyphenolics Prevent A{beta} Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer's Disease.
J. Wang, L. Ho, W. Zhao, K. Ono, C. Rosensweig, L. Chen, N. Humala, D. B. Teplow, and G. M. Pasinetti (2008)
J. Neurosci. 28, 6388-6392
   Abstract »    Full Text »    PDF »
Protein Kinase C{epsilon} Binds Peripherin and Induces Its Aggregation, Which Is Accompanied by Apoptosis of Neuroblastoma Cells.
L. Sunesson, U. Hellman, and C. Larsson (2008)
J. Biol. Chem. 283, 16653-16664
   Abstract »    Full Text »    PDF »
Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid {beta} Protein Production.
H. Shimizu, A. Tosaki, K. Kaneko, T. Hisano, T. Sakurai, and N. Nukina (2008)
Mol. Cell. Biol. 28, 3663-3671
   Abstract »    Full Text »    PDF »


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