Atypical PKC controls β-secretase expression and thereby regulates production of Alzheimer plaque precursor Aβ in brain and insulin receptor degradation in liver.

Background: Atypical PKC(aPKC) is elevated in livers of high-fat-fed mice and obese/T2DM humans; aPKC increases expression of lipogenic and gluconeogenic enzymes; aPKC inhibition/deficiency reverses these aberrations. However, hepatic insulin receptors (IRs) are also down-regulated and IR dysfunction is reversed by aPKC inhibition/deficiency. Recently, it was reported that the ectodomain of the hepatic IR is degraded by BACE1 [an aspartyl-peptidase required for Aβ-peptide/plaque formation in Alzheimer’s disease], and BACE1 levels are increased in livers of high-fat-fed mice and T2D humans. This is important as hyperinsulinemia increases Aβ-peptides by aPKC-dependent activation of BACE1. Objective: We questioned whether BACE1 expression is aPKC dependent. Methods: aPKC-λ was chemically-inhibited or heterozygously-knocked out (HλKO) in chow-fed or high-fat-fed hyperinsulinemic mice. Results: In brain (containing only PKC-λ), BACE1 mRNA/protein levels were reduced by 90% in HλKO mice, thus blocking increases in Aβ-peptide production provoked by acute insulin treatment in chow-fed mice and chronic hyperinsulinemia in high-fat-fed mice. In liver (containing PKC-λ and PKC-ζ) BACE1 expression was reduced by 40-50% in HλKO mice, but high-dose administration of liver-selective aPKC inhibitor decreased total aPKC activity and BACE1 expression by >90%, and lower “therapeutic” doses (sufficient to reverse hepatic IR and post-IR aberrations) fully/largely blocked high-fat-diet-induced increases in BACE1 expression. Conclusions: aPKC tightly controls BACE1 levels in liver and brain; in liver, aPKC excess in obesity and T2D provokes insulin resistance by altering IR and post-IR processes; in brain, aPKC excess abets AD development. Fortunately, BACE1 expression is selectively reduced in brain by nasally-administered aPKC inhibitor, and, in liver, by orally/subcutaneously-administered aPKC inhibitor.