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

Du et al. demonstrate that PKCδ modulates BACE1 expression and amyloidogenic amyloid precursor protein processing. Inhibition of PKCδ markedly reduces BACE1 expression, β-amyloid levels, and amyloid plaque formation and also rescues cognitive deficits in Alzheimer disease mouse models.
β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ 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 PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.
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