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J. Biol. Chem., Vol. 281, Issue 38, 28079-28089, September 22, 2006

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-Amyloid-induced Dynamin 1 Degradation Is Mediated by N-Methyl-D-Aspartate Receptors in Hippocampal Neurons^*

Brent L. Kelly¹ and Adriana Ferreira²

From the Department of Cell and Molecular Biology, Feinberg School of Medicine and the Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611

Alzheimer disease (AD) is a progressive, neurodegenerative disorder that leads to debilitating cognitive deficits. Although little is known about the early functional or ultrastructural changes associated with AD, it has been proposed that a stage of synaptic dysfunction might precede neurodegeneration in the development of this disease. Unfortunately, the molecular mechanisms that underlie such synaptic dysfunction remain largely unknown. Recently we have shown that -amyloid (A), the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that plays a critical role in synaptic vesicle recycling, and hence, in the signaling properties of the synapse. We report here that this dynamin 1 degradation was the result of calpain activation induced by the sustained calcium influx mediated by N-methyl-D-aspartate receptors in hippocampal neurons. In addition, our results showed that soluble oligomeric A, and not fibrillar A, was responsible for this sustained calcium influx, calpain activation, and dynamin 1 degradation. Considering the importance of dynamin 1 to synaptic function, these data suggest that A soluble oligomers might catalyze a stage of synaptic dysfunction that precedes synapse loss and neurodegeneration. These data also highlight the calpain system as a novel therapeutic target for early stage AD intervention.

Received for publication, May 26, 2006 , and in revised form, July 17, 2006.

^* This study was supported by Grant NS39080 from the National Institutes of Health (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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Supported in part by NIA/AG20506 Training Grant and an American Foundation for Aging Research Fellowship.

² To whom correspondence should be addressed: Northwestern Institute for Neuroscience, Northwestern University, Chicago, IL 60611. Tel.: 312-503-0597; Fax: 312-503-7345; E-mail: a-ferreira{at}northwestern.edu.

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