Journal
NEUROBIOLOGY OF DISEASE
Volume 46, Issue 1, Pages 52-58Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.12.043
Keywords
Alzheimer's disease; Diabetes; Tau phosphorylation; Sitagliptin; Dipeptidyl peptidase (DPP)-IV
Categories
Funding
- National Research Foundation of Korea
- Korea Health Technology
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [20100002859]
- Asan Institute for Life Sciences, Seoul, Korea [11-501]
- Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A100047]
- Korea Health Promotion Institute [A100047] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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, GSK3 beta (glycogen synthase kinase 3 beta). 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. (C) 2012 Elsevier Inc. All rights reserved.
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