AUTHOR=Song Xiangwei , Sun Yingqi , Wang Zhun , Su Yingying , Wang Yangkun , Wang Xueli 

TITLE=Exendin-4 alleviates β-Amyloid peptide toxicity via DAF-16 in a Caenorhabditis elegans model of Alzheimer's disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 14 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.955113

DOI=10.3389/fnagi.2022.955113

ISSN=1663-4365

ABSTRACT=Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD). They share common pathophysiological mechanisms. Thus, it has been increasingly suggested that several anti-T2DM drugs may have a therapeutic potential in AD. Exendin-4, as a GLP-1 receptor agonist, is an approved drug used to treat T2DM. In this research, the neuroprotective effect of Exendin-4 was investigated for the first time using transgenic Caenorhabditis elegans (C. elegans).
Our results demonstrated that Exendin-4 attenuated the amyloid-β (1-42) (Aβ1-42) toxicity via multiple mechanisms, such as depressing its expression on protein and mRNA, reducing Aβ(1-42) accumulation. Exendin-4 at 0.5 mg/ml had been shown to extend life by 34.39% in CL4176 and delay the onset of paralysis in CL4176 and CL2006 were increased by 8.18% and 8.02%  respectively.
With the treatment of Exendin-4, the nuclear translocation of DAF-16 in the transgenic nematode TJ356 was enhanced. SOD-3 as a downstream target gene regulated by DAF-16, was up-regulated on mRNA level and activity. ROS level was decreased. Another hand, we observed that the ability of Exendin-4 to regulate SOD was decreased in CL4176 worms with DAF-16 gene silenced. The activity of SOD and mRNA level of sod-3 were down-regulated by 30.45% and 43.13% respectively.
Taken together, Exendin-4 attenuated Aβ(1-42) toxicity in the C.elegans model of AD via decreasing the expression and the accumulation of Aβ(1-42). Exendin-4 exhibited the ability of antioxidant stress through DAF-16. With the continuous research, Exendin-4 would become a potential therapeutic strategy for treating AD.