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J. Biol. Chem., Vol. 280, Issue 36, 31746-31753, September 9, 2005

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-Amyloid-induced Dynamin 1 Depletion in Hippocampal Neurons

A POTENTIAL MECHANISM FOR EARLY COGNITIVE DECLINE IN ALZHEIMER DISEASE^*

Brent L. Kelly, Robert Vassar, and Adriana Ferreira¶||

From the Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University and the ^¶Institute for Neuroscience, Northwestern University, Chicago, Illinois 6061

Synaptic dysfunction is one of the earliest events in the pathogenesis of Alzheimer disease (AD). However, the molecular mechanisms underlying synaptic defects in AD are largely unknown. We report here that -amyloid (A), the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that is essential for synaptic vesicle recycling and, hence, for memory formation and information processing. The A-induced dynamin 1 decrease occurred in the absence of overt synaptic loss and was also observed in the Tg2576 mouse model of AD. In addition, our results provided evidence that the A-induced decrease in dynamin 1 was likely the result of a calpain-mediated cleavage of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. These data suggest a mechanism to explain the early cognitive loss without a major decline in synapse number observed in AD and propose a novel therapeutic target for AD intervention.

Received for publication, March 24, 2005 , and in revised form, June 17, 2005.

^* This study was supported in part by NIA, National Institutes of Health Grant R01A G022560 (to R. V.), National Institutes of Health Grant NS39080, and an Alzheimer's Association Investigator-initiated Research Grant (to A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by NIA, National Institutes of Health Training Grant AG20506 and a fellowship from the American Foundation for Aging Research.

^|| To whom correspondence should be addressed. Tel.: 312-503-0597; Fax: 312-503-7345; E-mail: a-ferreira{at}northwestern.edu.

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