Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures

Neurobiol Dis. 2012 Apr;46(1):52-8. doi: 10.1016/j.nbd.2011.12.043. Epub 2012 Jan 8.


Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. In this context, anti-diabetic agents such as rosiglitazone and glucagon-like peptide (GLP)-1 have been reported to reduce pathologies associated with AD, including tau hyperphosphorylation, suggesting that such agents might be used to treat AD. One such anti-diabetic agent is sitagliptin, which acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels. Given this action, sitagliptin would be predicted to reduce AD pathology. Accordingly, we investigated whether sitagliptin is effective in attenuating AD pathologies, focusing on tau phosphorylation in the OLETF type 2 diabetic rat model. Unexpectedly, we found that sitagliptin was not effective against pathological tau phosphorylation in the hippocampus of OLETF type 2 diabetes rats, and instead aggravated it. This paradoxically increased tau phosphorylation was attributed to activation of the tau kinase, GSK3β (glycogen synthase kinase 3β). Sitagliptin also increased ser-616 phosphorylation of the insulin receptor substrate (IRS)-1, suggesting increased insulin resistance in the brain. These phenomena were recapitulated in primary rat cortical neurons treated with sitagliptin, further confirming sitagliptin's effects on AD-related pathologies in neurons. These results highlight the need for caution in considering the use of sitagliptin in AD therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Diabetes Complications / chemically induced*
  • Diabetes Complications / metabolism*
  • Diabetes Complications / pathology
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / toxicity
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Male
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / pathology
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Pyrazines / toxicity*
  • Rats
  • Rats, Inbred OLETF
  • Rats, Long-Evans
  • Sitagliptin Phosphate
  • Triazoles / toxicity*
  • tau Proteins / metabolism*


  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyrazines
  • Triazoles
  • tau Proteins
  • Sitagliptin Phosphate