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

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 r...

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Published in:Phytotherapy research 2022-03, Vol.36 (3), p.1297-1309
Main Authors: Li, Zongyang, Zhang, Yuan, Meng, Xiangbao, Li, Min, Cao, Weiwei, Yang, Junshan, Xu, Xudong, Liu, Wenlan, Li, Weiping, Cai, Qian, Wang, Sicen, Ma, Guoxu, Liu, Zhiheng, Huang, Guodong
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Amyloid beta-Protein Precursor - pharmacology
Animals
Brain
Cognition
Cognitive ability
Cognitive Dysfunction - drug therapy
Deoxyglucose
dipeptidyl peptidase‐4
Dipeptidyl-peptidase IV
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Disease Models, Animal
Glucagon
Glucagon-Like Peptide 1 - metabolism
Glucagon-Like Peptide 1 - pharmacology
Glucagon-Like Peptide 1 - therapeutic use
glucagon‐like peptide‐1
Glucose
Glucose - metabolism
Glucose transporter
Hippocampus
Inflammation
Inhibitors
Insulin
Mice
Mice, Transgenic
Microglia
micro‐positron emission tomography
Neurodegenerative diseases
Neuroimaging
Peptidase
Peptidases
Peptides
Phosphorylation
Positron emission
Positron emission tomography
Presenilin 1
Receptors
Senile plaques
Tau protein
Tomography
Transgenic animals
Transgenic mice
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Summary: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.
ISSN:0951-418X
1099-1573
DOI:10.1002/ptr.7387