title: 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.
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 tau levels were increased in ob/ob mice and T2DM monkeys. Importantly, with correction of hyperinsulinemia by inhibition of hepatic aPKC and improvement in systemic insulin resistance, brain insulin signaling normalized. As FOXOs and PGC-1α are essential for memory and long-term neuronal function and regeneration and as Aβ1-40/42 and phospho-tau may increase interneuronal plaques and intraneuronal tangles, presently observed aberrations in hyperinsulinemic states may participate in linking insulin resistance to AD.
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Mini
authors.initials: M
authors.lastname: Sajan
authors.affiliation: Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hansen
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL.
authors.forename: Robert
authors.initials: R
authors.lastname: Ivey
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL.
authors.forename: Joshua
authors.initials: J
authors.lastname: Sajan
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL.
authors.forename: Csilla
authors.initials: C
authors.lastname: Ari
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL.
authors.forename: Shijie
authors.initials: S
authors.lastname: Song
authors.affiliation: The Biotechnology Centre of Oslo, Oslo, Norway.
authors.forename: Ursula
authors.initials: U
authors.lastname: Braun
authors.affiliation: The Biotechnology Centre of Oslo, Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL.
authors.forename: Margaret
authors.initials: M
authors.lastname: Farese-Higgs
authors.affiliation: Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL rfarese@health.usf.edu.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; D007328:Insulin; D010446:Peptide Fragments; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D051057:Proto-Oncogene Proteins c-akt; C115015:PKC-3 protein; D011493:Protein Kinase C