title: AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo.
abstract: Neurofibrillary tangles (NFTs) are the pathological hallmark of neurodegenerative diseases commonly known as tauopathies. NFTs result from the intracellular aggregation of abnormally and hyperphosphorylated tau proteins. Tau functions, which include the regulation of microtubules dynamics, are dependent on its phosphorylation status. As a consequence, any changes in tau phosphorylation can have major impacts on synaptic plasticity and memory. Recently, it has been demonstrated that AMP-activated protein kinase (AMPK) was deregulated in the brain of Alzheimer's disease (AD) patients where it co-localized with phosphorylated tau in pre-tangle and tangle-bearing neurons. Besides, it was found that AMPK was a tau kinase in vitro. Here, we find that endogenous AMPK activation in mouse primary neurons induced an increase of tau phosphorylation at multiple sites, whereas AMPK inhibition led to a rapid decrease of tau phosphorylation. We further show that AMPK mice deficient for one of the catalytic alpha subunits displayed reduced endogenous tau phosphorylation. Finally, we found that AMPK deficiency reduced tau pathology in the PS19 mouse model of tauopathy. These results show that AMPK regulates tau phosphorylation in mouse primary neurons as well as in vivo, and thus suggest that AMPK could be a key player in the development of AD pathology.
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT, F-59000 Lille, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Domise
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT, F-59000 Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Didier
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT, F-59000 Lille, France.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marinangeli
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chandakkar
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT, F-59000 Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Institut Cochin, Inserm U1016, Paris 75014, France.|CNRS, UMR 8104, Paris 75014, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT, F-59000 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D055372:AMP-Activated Protein Kinases