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 β-amyloid precursor protein (APP) plays a key role in Alzheimer disease neuropathogenesis. APP is cleaved by β- and α-secretase to produce APP-C99 and APP-C83, which are further cleaved by γ-secretase to produce amyloid β-protein (Aβ) and p3, respectively. APP adaptor proteins with phosphotyrosine-binding domains, including X11α (MINT1, encoded by gene APBA1) and X11β (MINT2, encoded by gene APBA2), can bind to the conserved YENPTY motif in the APP C terminus. Overexpression of X11α and X11β alters APP processing and Aβ production. Here, for the first time, we have described the effects of RNA interference (RNAi) silencing of X11α and X11β expression on APP processing and Aβ 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 Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. RNAi silencing of APBA2 also lowered Aβ levels, but apparently not via attenuation of γ-secretase cleavage of APP. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor protein X11α is particularly attractive with regard to therapeutic potential given that side effects of γ-secretase inhibition due to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.