The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice
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 &a...
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doaj-c12230b4b9664112ac7d3db120dd51c52020-11-25T00:47:02ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-05-012010253910.3390/ijms20102539ijms20102539The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model MiceYuriko Nakaoku0Satoshi Saito1Yumi Yamamoto2Takakuni Maki3Ryosuke Takahashi4Masafumi Ihara5Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, JapanDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita 565-8565, JapanDepartment of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, JapanVascular 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.https://www.mdpi.com/1422-0067/20/10/2539dipeptidyl peptidase-4 inhibitorshigh-fat dietspatial reference memorycerebral blood flowtau |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuriko Nakaoku Satoshi Saito Yumi Yamamoto Takakuni Maki Ryosuke Takahashi Masafumi Ihara |
spellingShingle |
Yuriko Nakaoku Satoshi Saito Yumi Yamamoto Takakuni Maki Ryosuke Takahashi Masafumi Ihara The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice International Journal of Molecular Sciences dipeptidyl peptidase-4 inhibitors high-fat diet spatial reference memory cerebral blood flow tau |
author_facet |
Yuriko Nakaoku Satoshi Saito Yumi Yamamoto Takakuni Maki Ryosuke Takahashi Masafumi Ihara |
author_sort |
Yuriko Nakaoku |
title |
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice |
title_short |
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice |
title_full |
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice |
title_fullStr |
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice |
title_full_unstemmed |
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice |
title_sort |
dipeptidyl peptidase-4 inhibitor linagliptin ameliorates high-fat induced cognitive decline in tauopathy model mice |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-05-01 |
description |
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. |
topic |
dipeptidyl peptidase-4 inhibitors high-fat diet spatial reference memory cerebral blood flow tau |
url |
https://www.mdpi.com/1422-0067/20/10/2539 |
work_keys_str_mv |
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