Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ 1–40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease

摘要

Abstract Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ 1–40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ 1–40/42 , β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), β-secretase, and Aβ 1–40/42 , and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ 1–40/42 . Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-ι/λ activation by insulin, metformin, or expression of constitutive PKC-ι provoked increases in β-secretase, Aβ 1–40/42 , and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt inhibitor. PKC-λ/ι provokes increases in brain β-secretase, Aβ 1–40/42 , and phospho-thr-231-tau. Excessive signaling via PKC-λ/ι may link hyperinsulinemia and other PKC-λ/ι activators to pathological and functional abnormalities in Alzheimer's disease. Graphical abstract Schematic of pathogenesis of neuronal signaling abnormalities in insulin-resistant states that lead to production of factors that may abet development of Alzheimer's disease. In this scheme, diet-induced increases in hepatic aPKC activity lead to impaired Akt activation by insulin, that is, hepatic insulin resistance (IR), increases in hepatic gluconeogenesis, systemic IR, and hyperinsulinemia, which persistently hyperactivates brain Akt and aPKC. Increases in brain Akt activity lead to phosphorylation and thus diminished activities of all FoxOs (1/3a/4/6) and decreased activity and expression of PGC-1α (all needed for neuronal function and integrity). Increases in brain aPKC activity, either directly or indirectly, provoke increases in β-secretase activity, and levels of Aβ 1-40/42 and phospho-thr-231-tau, and thus abet plaque and tangle development. Display Omitted