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The Journal of Neuroscience, December 27, 2006, 26(52):13428-13436; doi:10.1523/JNEUROSCI.4180-06.2006

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Neurobiology of Disease
Deficits in Synaptic Transmission and Learning in Amyloid Precursor Protein (APP) Transgenic Mice Require C-Terminal Cleavage of APP

Michael J. Saganich,^1 * Brock E. Schroeder,^2 * Veronica Galvan,³ Dale E. Bredesen,³ Edward H. Koo,² and Stephen F. Heinemann¹

¹Salk Institute for Biological Studies, La Jolla, California 92037, ²Department of Neurosciences, University of California at San Diego, La Jolla, California 92037, and ³Buck Institute for Age Research, Novato, California 94945

Correspondence should be addressed to Dr. Michael J. Saganich, Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: saganich{at}salk.edu

Synaptic dysfunction has been shown to be one of the earliest correlates of disease progression in animal models of Alzheimer's disease. Amyloid-ß protein (Aß) is thought to play an important role in disease-related synaptic dysfunction, but the mechanism by which Aß leads to synaptic dysfunction is not understood. Here we describe evidence that cleavage of APP in the C terminus may be necessary for the deficits present in APP transgenic mice. In APP transgenic mice with a mutated cleavage site at amino acid 664, normal synaptic transmission, synaptic plasticity, and learning were maintained despite the presence of elevated levels of APP, Aß₄₂, and even plaque accumulation. These results indicate that cleavage of APP may play a critical role in the development of synaptic and behavioral dysfunction in APP transgenic mice.

Key words: Aß-peptide; potentiation; Schaffer collateral terminals; synaptic plasticity; hippocampus; learning memory; spatial memory; LTP; amyloid; Alzheimer's disease

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Received May 15, 2006; revised Nov. 13, 2006; accepted Nov. 16, 2006.

Correspondence should be addressed to Dr. Michael J. Saganich, Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: saganich{at}salk.edu

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