TY - JOUR
T1 - A novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake
AU - Li, Zongyang
AU - Zhang, Yuan
AU - Meng, Xiangbao
AU - Li, Min
AU - Cao, Weiwei
AU - Yang, Junshan
AU - Xu, Xudong
AU - Liu, Wenlan
AU - Li, Weiping
AU - Cai, Qian
AU - Wang, Sicen
AU - Ma, Guoxu
AU - Liu, Zhiheng
AU - Huang, Guodong
N1 - Funding Information:
This project was supported by the Research Fund from Shenzhen Key Laboratory of Neurosurgery (ZDSYS20140509173142601), the Shenzhen Development and Reform Commissions Stroke Screening and Prevention Public Service Platform improving program, China Postdoctoral Science Foundation (2021M702285), the National Natural Science Foundation of China (81503290, 81772685, 81902522, 81760227 and 81703558), Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases, Natural Science Foundation of Guangdong Province (2018A030310647 and 2019A1515010311), the Basic research projects (subject arrangement) of Shenzhen Science and Technology Program (JCYJ20170413173149177 and JCYJ20180507184656626), and Shenzhen Double Chain Grant [2018]256.
Funding Information:
National Natural Science Foundation of China, Grant/Award Numbers: 81503290, 81772685, 81902522, 81760227, 8170355; Shenzhen Double Chain Grant, Grant/Award Number: [2018]256; the Research Fund from Shenzhen Key Laboratory of Neurosurgery, Grant/Award Number: ZDSYS20140509173142601; China Postdoctoral Science Foundation, Grant/Award Number: 2021M702285; Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases; Natural Science Foundation of Guangdong Province, Grant/Award Numbers: 2018A030310647, 2019A1515010311; the Basic research projects (subject arrangement) of Shenzhen Science and Technology Program, Grant/Award Numbers: JCYJ20170413173149177, JCYJ20180507184656626; the Shenzhen Development and Reform Commissions Stroke Screening and Prevention Public Service Platform improving program Funding information
Publisher Copyright:
© 2022 John Wiley & Sons Ltd.
PY - 2022/3
Y1 - 2022/3
N2 - Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aβ plaques as well as the insoluble and soluble forms of Aβ40 and Aβ42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.
AB - Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aβ plaques as well as the insoluble and soluble forms of Aβ40 and Aβ42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.
KW - Alzheimer's disease
KW - dipeptidyl peptidase-4
KW - glucagon-like peptide-1
KW - micro-positron emission tomography
KW - Brain
KW - Glucagon-Like Peptide 1/metabolism
KW - Mice, Transgenic
KW - Cognition
KW - Animals
KW - Amyloid beta-Protein Precursor/genetics
KW - Cognitive Dysfunction/drug therapy
KW - Alzheimer Disease/drug therapy
KW - Glucose/metabolism
KW - Mice
KW - Dipeptidyl-Peptidase IV Inhibitors/pharmacology
KW - Amyloid beta-Peptides/metabolism
KW - Hippocampus
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85123797667&partnerID=8YFLogxK
U2 - 10.1002/ptr.7387
DO - 10.1002/ptr.7387
M3 - Journal article
C2 - 35088915
AN - SCOPUS:85123797667
SN - 0951-418X
VL - 36
SP - 1297
EP - 1309
JO - Phytotherapy Research
JF - Phytotherapy Research
IS - 3
ER -