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J. Biol. Chem., Vol. 279, Issue 47, 49099-49104, November 19, 2004

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The Neuronal Adaptor Protein X11 Reduces Amyloid -Protein Levels and Amyloid Plaque Formation in the Brains of Transgenic Mice^*

Ju-Hyun Lee, Kwok-Fai Lau, Michael S. Perkinton, Claire L. Standen, Boris Rogelj, Agnieszka Falinska, Declan M. McLoughlin, and Christopher C. J. Miller

From the Department of Neuroscience and Section of Old Age Psychiatry, The Institute of Psychiatry, King's College London SE5 8AF, United Kingdom

Accumulation of cerebral amyloid -protein (A) is believed to be part of the pathogenic process in Alzheimer's disease. A is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11, a neuronal adaptor protein. X11 has been shown to inhibit the production of A in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11 can also inhibit the deposition of A as amyloid plaques is not known. Here we show that transgenic overexpression of X11 in neurons leads to a decrease in cerebral A levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11 retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11 function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.

Received for publication, May 19, 2004 , and in revised form, September 1, 2004.

^* This work was supported by grants from the Medical Research Council, Wellcome Trust, European Union Fifth Framework, Research into Aging, The Health Foundation, and the Alzheimer's Disease Society. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Neuroscience, P. O. Box P037, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. Tel.: 44-207-8480393; Fax: 44-207-7080017; E-mail: chris.miller{at}iop.kcl.ac.uk.

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