Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice

Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic ?-amyloid (A?) peptide generated from proteolytic cleavage of ?-amyloid protein precursor (APP). Except for familial AD arising from mutations in theAPPand presenilin (PSEN) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein ?/calsyntenin1 (ALC?/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALC??X11L?APP tripartite complex suppresses A? generationin vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALC? in APP metabolismin vivoremains unclear. Here, by generating ALC?-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALC? in the suppression of amyloidogenic processing of endogenous APPin vivo. We observed that ALC? deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic ?-site cleavage of APP, especially in endosomes, and increases the generation of endogenous A? in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALC?-deficient background. These results unveil a potential role of ALC? in protecting cerebral neurons from A?-dependent pathogenicity in AD.