Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1−40/42 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.

Publication date: Available online 15 September 2017
Source:Neurobiology of Aging
Author(s): Mini P. Sajan, Barbara C. Hansen, Margaret G. Higgs, C. Ron Kahn, Ursula Braun, Michael Leitges, Collin R. Park, David M. Diamond, Robert V. Farese
IntroductionHyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ1−40/42 and phospho-tau in insulin-resistant animals.MethodsHere, we examined underlying mechanisms in mice, neuronal cells and mouse hippocampal slices.ResultsLike Aβ1−40/42, β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι is sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, aPKC, β-secretase and Aβ1−40/42, and restored acute Akt activation ; However, two aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ1−40/42. 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, Aβ1−40/42 and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt, inhibitor.ConclusionsPKC-λ/ι provokes increases in brain β-secretase, Aβ1−40/42 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.

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