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

Zongyang Li, Yuan Zhang, Xiangbao Meng, Min Li, Weiwei Cao, Junshan Yang, Xudong Xu, Wenlan Liu, Weiping Li, Qian Cai, Sicen Wang, Guoxu Ma*, Zhiheng Liu*, Guodong Huang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1297-1309
Number of pages13
JournalPhytotherapy Research
Volume36
Issue number3
DOIs
Publication statusPublished - Mar 2022

Scopus Subject Areas

  • Pharmacology

User-Defined Keywords

  • Alzheimer's disease
  • dipeptidyl peptidase-4
  • glucagon-like peptide-1
  • micro-positron emission tomography
  • Brain
  • Glucagon-Like Peptide 1/metabolism
  • Mice, Transgenic
  • Cognition
  • Animals
  • Amyloid beta-Protein Precursor/genetics
  • Cognitive Dysfunction/drug therapy
  • Alzheimer Disease/drug therapy
  • Glucose/metabolism
  • Mice
  • Dipeptidyl-Peptidase IV Inhibitors/pharmacology
  • Amyloid beta-Peptides/metabolism
  • Hippocampus
  • Disease Models, Animal

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