Analysis of intracellular of APP metabolism and exploration of novel targets of drug suppressing Aβ generation

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The amyloid p-protein (Ap) is a component of amyloid plaques, one of the major hallmarks of Alzheimer's disease (AD), and is implicated in the pathology of AD. Ap is generated by proteolytic cleavage of the amyloid p-protein precursor (APP), an integral membrane protein with a short intracellular carboxyl terminus. The cytoplasmic tail of APP corresponds to the regulation of metabolism and/or intracellular transport of APP by interacting with cytoplasmic proteins. To revel the regulators in APP metabolism and to understand the regulatory mechanism are important to find novel target molecules for drug development suppressing Ap generation. We have isolated X11L, a neuron-specific adaptor protein, which binds to the cytoplasmic domain of APP and suppresses APP metabolism including Ap generation. We found that some extracellular stimulus activates XIlL and facilitates the association with APP. We identified regulatory motif on the amino-terminal half of X11L, while the middle PI domain bound to the APP. Our current observations showed that X11L can be activated by extracellular stimulus and that X11L is a potential candidate for drug development in the suppression of Ap generation.In contrast to these in vitro study with cells, it is sill unclear whether the X11L regulates APP metabolism in brain. To resolve this issue, we generated mutant mouse line lacking X11L expression (X11L-KO mouse). In the brain of this mutant mouse, the generation of CTFp, a amyloidogenic fragment of APP, and Ap increased when compared with it in the wild-type mouse brain. Our result clearly showed that X11L regulates APP metabolism physiologically in brain. Present results suggest that functional disorder of X11L in the aged brain may cause the pathogenesis of sporadic type of AD.