Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes.

摘要: β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage amyloid precursor (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase complex. Although activation some kinase C (PKC) isoforms such as PKCα e has been shown to regulate nonamyloidogenic pathways degradation, it unclear whether other PKC are involved APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression AD brain. knockdown reduces expression, BACE1-mediated processing, production. Conversely, overexpression increases generation. Importantly, inhibition rottlerin markedly levels, neuritic plaque formation rescues cognitive deficits an Swedish mutations K594N/M595L/presenilin-1 exon 9 deletion-transgenic mouse model. Our study indicates important aggravating pathogenesis, may be potential target therapeutics.