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      Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice.

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          Abstract

          Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.

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          Author and article information

          Journal
          Neurobiol. Dis.
          Neurobiology of disease
          1095-953X
          0969-9961
          Apr 2016
          : 88
          Affiliations
          [1 ] Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
          [2 ] Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
          [3 ] MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
          [4 ] Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada; Université Laval, Faculté de Pharmacie, Québec, Canada.
          [5 ] Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.
          [6 ] Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada. Electronic address: emmanuel@planel.org.
          Article
          S0969-9961(16)30005-5
          10.1016/j.nbd.2016.01.005
          26777665
          Copyright © 2016 Elsevier Inc. All rights reserved.

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