DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease

Cao, Yue and Hölscher, Christian and Hu, Meng-Ming and Wang, Ting and Zhao, Fang and Bai, Yu and Zhang, Jun and Wu, Mei-Na and Qi, Jin-Shun (2018) DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease. European Journal of Pharmacology, 827. pp. 215-226. ISSN 0014-2999

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3β in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

Item Type: Journal Article
Journal or Publication Title: European Journal of Pharmacology
Additional Information: This is the author’s version of a work that was accepted for publication in European Journal of Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in European Journal of Pharmacology, 827, 2018 DOI: 10.1016/j.ejphar.2018.03.024
Uncontrolled Keywords: /dk/atira/pure/subjectarea/asjc/3000/3004
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 124091
Deposited By: ep_importer_pure
Deposited On: 16 Mar 2018 15:02
Refereed?: Yes
Published?: Published
Last Modified: 17 Feb 2020 03:53
URI: https://eprints.lancs.ac.uk/id/eprint/124091

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