The neuronal adaptor protein X11β reduces amyloid β-protein levels and amyloid plaque formation in the brains of transgenic mice

Abstract

Accumulation of cerebral amyloid β-protein (Aβ) is believed to be part of the pathogenic process in Alzheimer's disease. Aβ 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 X11β, a neuronal adaptor protein. X11β has been shown to inhibit the production of Aβ in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11β can also inhibit the deposition of Aβ as amyloid plaques is not known. Here we show that transgenic overexpression of X11β in neurons leads to a decrease in cerebral Aβ levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11β retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11β function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.