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

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