Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6803213 | Neurobiology of Aging | 2018 | 40 Pages |
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 Aβ1-40/42 and phospho-thr-231-tau, and thus abet plaque and tangle development.178
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Authors
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,