RNA interference-mediated silencing of X11α and X11β attenuates amyloid β-protein levels via differential effects on β-amyloid precursor protein processing

Processing of the beta-amyloid precursor protein (APP) plays a key role in Alzheimer disease neuropathogenesis. APP is cleaved by beta- and alpha-secretase to produce APP-C99 and APP-C83, which are further cleaved by alpha-secretase to produce amyloid beta-protein (A beta) and p3, respectively. APP adaptor proteins with phosphotyrosine-binding domains, including XII alpha (MINT1, encoded by gene APBA1) and XII beta (MINT2, encoded by gene APBA2), can bind to the conserved YENPTY motif in the APP C terminus. Overexpression of XII alpha and XII beta alters APP processing and A beta production. Here, for the first time, we have described the effects of RNA interference (RNAi) silencing of XII alpha and XII beta expression on APP processing and A beta production. RNAi silencing of APBA1 in H4 human neuroglioma cells stably transfected to express either full-length APP or APP-C99 increased APP C-terminal fragment levels and lowered A beta levels in both cell lines by inhibiting gamma-secretase cleavage of APP. RNAi silencing of APBA2 also lowered A beta levels, but apparently not via attenuation of gamma-secretase cleavage of APP. The notion of attenuating gamma-secretase cleavage of APP via the APP adaptor protein XII alpha is particularly attractive with regard to therapeutic potential given that side effects of gamma-secretase inhibition due to impaired proteolysis of other gamma-secretase substrates, e.g. Notch, might be avoided.