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Science 25 October 2002:
Vol. 298. no. 5594, pp. 789 - 791
DOI: 10.1126/science.1074069
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Alzheimer's Disease Is a Synaptic Failure

Dennis J. Selkoe

In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta  protein.

Center for Neurologic Diseases, Brigham and Women's Hospital, and the Harvard Center for Neurodegeneration and Repair, Boston, MA 02115, USA. E-mail: selkoe{at}cnd.bwh.harvard.edu

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Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.
R. Kuwano, A. Miyashita, H. Arai, T. Asada, M. Imagawa, M. Shoji, S. Higuchi, K. Urakami, A. Kakita, H. Takahashi, et al. (2006)
Hum. Mol. Genet. 15, 2170-2182
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Neprilysin-sensitive Synapse-associated Amyloid-beta Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function.
S.-M. Huang, A. Mouri, H. Kokubo, R. Nakajima, T. Suemoto, M. Higuchi, M. Staufenbiel, Y. Noda, H. Yamaguchi, T. Nabeshima, et al. (2006)
J. Biol. Chem. 281, 17941-17951
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Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice..
J Svensson, M Diez, J Engel, C Wass, A Tivesten, J-O Jansson, O Isaksson, T Archer, T Hokfelt, and C Ohlsson (2006)
J. Endocrinol. 189, 617-627
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Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion.
T. H. Gillingwater, C. A. Ingham, K. E. Parry, A. K. Wright, J. E. Haley, T. M. Wishart, G. W. Arbuthnott, and R. R. Ribchester (2006)
Brain 129, 1546-1556
   Abstract »    Full Text »    PDF »
A{beta} induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597-624).
G. M. Shaked, M. P. Kummer, D. C. Lu, V. Galvan, D. E. Bredesen, and E. H. Koo (2006)
FASEB J 20, 1254-1256
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Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices..
N. Shahani, S. Subramaniam, T. Wolf, C. Tackenberg, and R. Brandt (2006)
J. Neurosci. 26, 6103-6114
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Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664.
V. Galvan, O. F. Gorostiza, S. Banwait, M. Ataie, A. V. Logvinova, S. Sitaraman, E. Carlson, S. A. Sagi, N. Chevallier, K. Jin, et al. (2006)
PNAS 103, 7130-7135
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Neuropathology of amnestic mild cognitive impairment..
H. V. Vinters (2006)
Arch Neurol 63, 645-646
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Synaptic Mitochondria Are More Susceptible to Ca2+Overload than Nonsynaptic Mitochondria.
M. R. Brown, P. G. Sullivan, and J. W. Geddes (2006)
J. Biol. Chem. 281, 11658-11668
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Beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner..
A. M. Floden and C. K. Combs (2006)
J. Neurosci. 26, 4644-4648
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Effects of secreted oligomers of amyloid {beta}-protein on hippocampal synaptic plasticity: a potent role for trimers.
M. Townsend, G. M. Shankar, T. Mehta, D. M. Walsh, and D. J. Selkoe (2006)
J. Physiol. 572, 477-492
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AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice.
E. H. Chang, M. J. Savage, D. G. Flood, J. M. Thomas, R. B. Levy, V. Mahadomrongkul, T. Shirao, C. Aoki, and P. T. Huerta (2006)
PNAS 103, 3410-3415
   Abstract »    Full Text »    PDF »
Development and Regulation of Dendritic Spine Synapses.
B. Calabrese, M. S. Wilson, and S. Halpain (2006)
Physiology 21, 38-47
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Temporal Profile of Amyloid-beta (Abeta) Oligomerization in an in Vivo Model of Alzheimer Disease: A LINK BETWEEN Abeta AND TAU PATHOLOGY.
S. Oddo, A. Caccamo, L. Tran, M. P. Lambert, C. G. Glabe, W. L. Klein, and F. M. LaFerla (2006)
J. Biol. Chem. 281, 1599-1604
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Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid {beta}-Peptide-induced Neuronal Apoptosis: SYNERGISTIC INVOLVEMENT OF CALPAIN AND CASPASE-3.
A. Fifre, I. Sponne, V. Koziel, B. Kriem, F. T. Y. Potin, B. E. Bihain, J.-L. Olivier, T. Oster, and T. Pillot (2006)
J. Biol. Chem. 281, 229-240
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The corpus callosum in Pick's disease, Alzheimer's disease, and amyotrophic lateral sclerosis: Gliosis implies possible clinical consequence.
C. Murray, A. Viehman, and C. F. Lippa (2006)
American Journal of Alzheimer's Disease and Other Dementias 21, 37-43
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GSK-3beta Directly Phosphorylates and Activates MARK2/PAR-1.
S. Kosuga, E. Tashiro, T. Kajioka, M. Ueki, Y. Shimizu, and M. Imoto (2005)
J. Biol. Chem. 280, 42715-42722
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