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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

文献作者：YueCao, Christian H?lscher, Meng-Ming Hu, Ting Wang, Fang Zhao, Yu Bai, Jun Zhang, Mei-Na Wu, Jin-Shun Qi   《European Journal of Pharmacology》

ABSTRACTS
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.
KEY WORDS
GLP-1/GIP dual agonist; APP/PS1 AD mice; Working memory; Long term memory; L-LTP; Amyloid-β protein; Phosphorylated tau protein; PI3K/AKT/GSK3β
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RELATED PRODUCTS
The dual agonist DA5-CH was gotten from Chinapeptides Ltd (Shanghai, China).
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https://www.sciencedirect.com/science/article/pii/S001429991830178X
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