Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1α and Increases in Aβ1-40/42 and Phospho-Tau May Abet Alzheimer Development

Diabetes
Mini P SajanRobert V Farese

Abstract

Increased coexistence of Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) suggests that insulin resistance abets neurodegenerative processes, but linkage mechanisms are obscure. Here, we examined insulin signaling factors in brains of insulin-resistant high-fat-fed mice, ob/ob mice, mice with genetically impaired muscle glucose transport, and monkeys with diet-dependent long-standing obesity/T2DM. In each model, the resting/basal activities of insulin-regulated brain protein kinases, Akt and atypical protein kinase C (aPKC), were maximally increased. Moreover, Akt hyperactivation was accompanied by hyperphosphorylation of substrates glycogen synthase kinase-3β and mammalian target of rapamycin and FOXO proteins FOXO1, FOXO3A, and FOXO4 and decreased peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression. Akt hyperactivation was confirmed in individual neurons of anterocortical and hippocampal regions that house cognition/memory centers. Remarkably, β-amyloid (Aβ1-40/42) peptide levels were as follows: increased in the short term by insulin in normal mice, increased basally in insulin-resistant mice and monkeys, and accompanied by diminished amyloid precursor protein in monkeys. Phosphorylated ...Continue Reading

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Citations

Jul 20, 2016·The Journal of Experimental Medicine·Molly StanleyDavid M Holtzman
May 31, 2020·Molecular Neurodegeneration·Wenzhang WangXiongwei Zhu
Dec 24, 2018·Aging·Robert V Farese, Mini P Sajan
Dec 20, 2018·Brain Plasticity·A M FernandezI Torres Aleman
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Mar 3, 2020·Experimental Gerontology·Dae Hyun KimHae Young Chung
May 30, 2017·Neurochemistry International·Mitsuru Shinohara, Naoyuki Sato
Jun 26, 2021·Neurotoxicity Research·Sedigheh EskandariGholamreza Bahrami
Apr 24, 2021·Human Molecular Genetics·Montasir ElahiNobutaka Hattori
Aug 27, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Tomasz CharytoniukKarolina Konstantynowicz-Nowicka

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Methods Mentioned

BETA
transgenic

Software Mentioned

cellSens Dimension

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