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

Neurobiol Dis. 2016 Apr;88:55-65. doi: 10.1016/j.nbd.2016.01.005. Epub 2016 Jan 9.


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.

Keywords: Alzheimer's disease; Diabetes mellitus; Hippocampus; Hypothermia; Kinase; Phosphatase; Tau hyperphosphorylation; Temperature; Thermoregulation; db/db mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Analysis of Variance
  • Animals
  • Blood Glucose
  • Body Weight / genetics
  • Body Weight / physiology
  • Brain / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / therapy*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Glycemic Index
  • Hypothermia, Induced*
  • Insulin Resistance / genetics
  • Leptin / deficiency
  • Leptin / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Phosphorylation / genetics
  • Signal Transduction / genetics
  • tau Proteins / metabolism*


  • Blood Glucose
  • Leptin
  • tau Proteins
  • MAP Kinase Kinase 4