title: Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation.
abstract: Alzheimer's disease (AD) is a highly prevalent multifactorial disease for which Diabetes Mellitus (DM) is a risk factor. Abnormal phosphorylation and aggregation of tau is a key hallmark of AD. In animal models, DM induces or exacerbates the phosphorylation of tau, suggesting that DM may influence the risk at AD by directly facilitating tau pathology. Previously we reported that tau phosphorylation induced in response to metabolic stress is reversible. Since identification and understanding of early players in tau pathology is pivotal for therapeutic intervention, we here investigated the mechanism underlying tau phosphorylation in the diabetic brain and its potential for reversibility. To model DM we used streptozotocin-treatment to induce insulin deficiency in rats. Insulin depletion leads to increased tau phosphorylation in the brain and we investigated the activation status of known tau kinases and phosphatases in this model. We identified protein kinase A (PKA) as a tau kinase activated by DM in the brain. The potential relevance of this signaling pathway to AD pathogenesis is indicated by the increased level of active PKA in temporal cortex of early stage AD patients. Our data indicate that activation of PKA and tau phosphorylation are associated with insulin deficiency per se, rather than the downstream energy deprivation. In vitro studies confirm that insulin deficiency results in PKA activation and tau phosphorylation. Strikingly, both active PKA and induced tau phosphorylation are reversed upon insulin treatment in the steptozotocin animal model. Our data identify insulin deficiency as a direct trigger that induces the activity of the tau kinase PKA and results in tau phosphorylation. The reversibility upon insulin treatment underscores the potential of insulin as an early disease-modifying intervention in AD and other tauopathies.
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience VU University, Amsterdam, The Netherlands. Electronic address: judithvdharg@hotmail.com.
authors.forename: Judith M
authors.initials: JM
authors.lastname: van der Harg
authors.affiliation: Dept. Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: l.eggels@amc.uva.nl.
authors.forename: Leslie
authors.initials: L
authors.lastname: Eggels
authors.affiliation: Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience VU University, Amsterdam, The Netherlands; Dept. of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: fabian.bangel@gmail.com.
authors.forename: Fabian N
authors.initials: FN
authors.lastname: Bangel
authors.affiliation: Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience VU University, Amsterdam, The Netherlands. Electronic address: silvieruigrok@gmail.com.
authors.forename: Silvie R
authors.initials: SR
authors.lastname: Ruigrok
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: r.zwart@amc.uva.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Zwart
authors.affiliation: Dept. of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: JJM.Hoozemans@vumc.nl.
authors.forename: Jeroen J M
authors.initials: JJM
authors.lastname: Hoozemans
authors.affiliation: Dept. Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: s.e.lafleur@amc.uva.nl.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: la Fleur
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience VU University, Amsterdam, The Netherlands; Dept. of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: w.scheper@vumc.nl.
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007328:Insulin / Q000172:deficiency*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D007328:Insulin; C054369:MAPT protein, human; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Alzheimer's disease; Diabetes mellitus; Insulin deficiency; Phosphorylated tau; Protein kinase A