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J. Biol. Chem., Vol. 282, Issue 26, 18895-18906, June 29, 2007

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Internalized Antibodies to the A Domain of APP Reduce Neuronal A and Protect against Synaptic Alterations^*

From the Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021

Immunotherapy against -amyloid peptide (A) is a leading therapeutic direction for Alzheimer disease (AD). Experimental studies in transgenic mouse models of AD have demonstrated that A immunization reduces A plaque pathology and improves cognitive function. However, the biological mechanisms by which A antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with A antibodies decreases levels of intracellular A. Antibody-mediated reduction in cellular A appears to require that the antibody binds to the extracellular A domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with A antibodies protects against synaptic alterations that occur in APP mutant neurons.

Received for publication, January 12, 2007 , and in revised form, March 30, 2007.

^* This work was supported in part by the Dana Foundation, the Alzheimer's Association, the American Health Assistance Foundation, National Institutes of Health Grants NS045677 and AG028174 (to G. K. G.), and by a doctoral fellowship from Fundação para a Ciência e a Tecnologia, Portugal (to C. G. A.). 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–S12 and movie S1.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Dept. of Neurology & Neuroscience, Weill Medical College of Cornell University, 525 East 68th St. New York, NY 10021. Tel.: 212-746-6598; Fax: 212-746-8741; E-mail: gkgouras{at}med.cornell.edu.

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