title: MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.
abstract: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany julia.banzhaf@dzne.lmu.de dieter.edbauer@dzne.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Banzhaf-Strathmann
authors.affiliation: German Center for Neurodegenerative Diseases, c/o European Neuroscience Institute ENI-G, Göttingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Benito
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: May
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.affiliation: German Center for Neurodegenerative Diseases, c/o European Neuroscience Institute ENI-G, Göttingen, Germany Department of Psychiatry and Psychotherapy, University Medical Center, University Göttingen, Göttingen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.affiliation: German Center for Neurodegenerative Diseases, Munich, Germany Adolf Butenandt Institute, Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Munich Cluster of Systems Neurology (SyNergy), Munich, Germany julia.banzhaf@dzne.lmu.de dieter.edbauer@dzne.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Edbauer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics; D015536:Down-Regulation; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; C054369:MAPT protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D016875:tau Proteins; C517187:PPP1CA protein, human; D054645:Protein Phosphatase 1; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6
keywords: Alzheimer's disease; kinases; microRNA‐125b; phosphatases; tau phosphorylation