title: Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
authors.forename: Jae-Wan
authors.initials: JW
authors.lastname: Huh
authors.forename: Mi
authors.initials: M
authors.lastname: Jang
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Suh
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.forename: Jeong-Su
authors.initials: JS
authors.lastname: Park
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D048909:Diabetes Complications / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011719:Pyrazines / Q000633:toxicity*; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000633:toxicity*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D016875:tau Proteins; D000068900:Sitagliptin Phosphate