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The Journal of Neuroscience, August 5, 2009, 29(31):9704-9713; doi:10.1523/JNEUROSCI.2292-09.2009

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Neurobiology of Disease
Synaptic Activity Reduces Intraneuronal Aβ, Promotes APP Transport to Synapses, and Protects against Aβ-Related Synaptic Alterations

Davide Tampellini,¹ Nawreen Rahman,¹ Eduardo F. Gallo,¹ Zhenyong Huang,¹ Magali Dumont,¹ Estibaliz Capetillo-Zarate,¹ Tao Ma,¹ Rong Zheng,² Bao Lu,³ David M. Nanus,² Michael T. Lin,¹ and Gunnar K. Gouras^1,4

Departments of ¹Neurology and Neuroscience and ²Medicine, Weill Medical College of Cornell University, New York, New York 10065, ³Pulmonary Division, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ⁴Rockefeller University, New York, New York 10065

Correspondence should be addressed to Gunnar K. Gouras, Department of Neurology and Neuroscience, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065. Email: gkgouras{at}med.cornell.edu

A central question in Alzheimer's disease research is what role synaptic activity plays in the disease process. Synaptic activity has been shown to induce β-amyloid peptide release into the extracellular space, and extracellular β-amyloid has been shown to be toxic to synapses. We now provide evidence that the well established synaptotoxicity of extracellular β-amyloid requires -secretase processing of amyloid precursor protein. Recent evidence supports an important role for intraneuronal β-amyloid in the pathogenesis of Alzheimer's disease. We show that synaptic activity reduces intraneuronal β-amyloid and protects against β-amyloid-related synaptic alterations. We demonstrate that synaptic activity promotes the transport of the amyloid precursor protein to synapses using live cell imaging, and that the protease neprilysin is involved in reduction of intraneuronal β-amyloid with synaptic activity.

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Received May 14, 2009; revised June 19, 2009; accepted June 28, 2009.

Correspondence should be addressed to Gunnar K. Gouras, Department of Neurology and Neuroscience, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065. Email: gkgouras{at}med.cornell.edu

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