The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice

International Journal of Molecular Sciences

Yuriko Nakaoku¹  Ryosuke Takahashi¹  Takakuni Maki¹  Satoshi Saito²  Masafumi Ihara²  Yumi Yamamoto³ 

[1] Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan;Department of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan;Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan;

关键词: dipeptidyl peptidase-4 inhibitors;    high-fat diet;    spatial reference memory;    cerebral blood flow;    tau;   

DOI  :  10.3390/ijms20102539

来源: DOAJ

【 摘 要 】

Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer’s disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.

【 授权许可】

Unknown