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

• Published in: Neurobiology of aging 2018-01, Vol.61, p.225
• Main Authors: Sajan, Mini P, Hansen, Barbara C, Higgs, Margaret G, Kahn, C Ron, Braun, Ursula, Leitges, Michael, Park, Collin R, Diamond, David M, Farese, Robert V
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Brain - metabolism; Cells, Cultured; Hyperinsulinism - etiology; Isoenzymes - metabolism; Male; Memory; Mice, Inbred C57BL; Neurons - metabolism; Peptide Fragments - metabolism; Phosphorylation; Protein Kinase C - metabolism; tau Proteins - metabolism
• ISSN: 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.09.001

Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ , 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 , 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 . 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 , 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 , 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.