Faculty Collaboration Database

A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease. Hippocampus 2018 May;28(5):358-372

Date

02/24/2018

Pubmed ID

29473979

DOI

10.1002/hipo.22837

Scopus ID

2-s2.0-85043296650 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of ^S133 p-CREB, ^T286 p-CAMKII and ^S9 p-GSK3β in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Author List

Li T, Jiao JJ, Hölscher C, Wu MN, Zhang J, Tong JQ, Dong XF, Qu XS, Cao Y, Cai HY, Su Q, Qi JS

Author

Jiaqing Tong PhD Postdoctoral Researcher 3 in the Neurology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Animals
Blood Glucose
Body Weight
Cognition Disorders
Disease Models, Animal
Female
Gene Expression
Glucagon-Like Peptide 1
Hippocampus
Long-Term Potentiation
Male
Memory
Mice, Inbred C57BL
Mice, Transgenic
Neuroprotective Agents
Nootropic Agents
Receptors, Gastrointestinal Hormone
Receptors, Glucagon