CPNE7 Regulates Amyloidogenesis Through CAP1-Dependent ADAM10 Translation

Abstract

The accumulation of amyloid plaques is a pathological hallmark of Alzheimer's disease (AD), in which ADAM10, the α-secretase that catalyzes APP and facilitates the non-amyloidogenesis pathway, plays an important role. We have previously reported that the expression of copine-7 (Cpne7) in the hippocampus of APP/PS1 mice is significantly upregulated by nicotine, whereas the potential role of CPNE7 in AD remains largely unknown. Here, we report that CPNE7 protein levels are significantly decreased in APP/PS1 mice and HEK293 cells stably expressing full-length APP. CPNE7 is shown to reduce Aβ levels by favoring ADAM10 activity, and the elevated ADAM10 protein by CPNE7 involves a translational mechanism. Further transcriptome profiling reveals that CPNE7 differentially regulates genes associated with neuronal function. Among these, cyclase-associated actin cytoskeleton regulatory protein 1 (CAP1) is identified as a target gene of CPNE7, which controls ADAM10 translation through binding to the 5′ untranslated region (5′UTR). Collectively, the CPNE7-CAP1 axis could be critical in the amyloidogenic pathway by regulating ADAM10 translation, in which the RNA binding activity of CAP1 is highlighted.