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

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.