title: Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation.
abstract: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia, and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism. In this report, we examined the role of IR on the regulation of AMPK phosphorylation and AMPK-mediated Tau phosphorylation. We found that AMPK(Ser-485), but not AMPK(Thr-172), phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), induced AMPK phosphorylation at both Thr-172 and Ser-485. AMPK activation also triggered Tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPK(Ser-485), but not AMPK(Thr-172), hyperphosphorylation whereas AICAR-induced Tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPK(Ser-485) hyperphosphorylation and restored AMPK-mediated Tau dephosphorylation. Transfection of AMPK(S485A) mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR → chronic overactivation of Akt → AMPK(Ser-485) hyperphosphorylation → inhibition of AMPK-mediated Tau dephosphorylation. Together, our results show for the first time a possible contribution of IR-induced AMPK(Ser-485) phosphorylation to the increased risk of AD in obesity and diabetes.
authors.affiliation: From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 bhumsoo@umich.edu.
authors.forename: Bhumsoo
authors.initials: B
authors.lastname: Kim
authors.affiliation: From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Claudia
authors.initials: C
authors.lastname: Figueroa-Romero
authors.affiliation: From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Crystal
authors.initials: C
authors.lastname: Pacut
authors.affiliation: From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Carey
authors.initials: C
authors.lastname: Backus
authors.affiliation: From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000263:Adenylate Kinase / Q000502:physiology*; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D048909:Diabetes Complications / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D006801:Humans; D007333:Insulin Resistance; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012307:Risk Factors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D010768:Phosphoserine; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase
keywords: Alzheimer disease; insulin resistance; metabolic syndrome; neuron; phosphorylation