<scp>IL</scp> ‐ <scp>17A</scp> Induces Circadian Disruptions Through the Epigenetic Repression of <scp>BMAL1</scp> in Mice With Alzheimer's Disease

Circadian disruptions and neuroinflammation impact nearly all people with Alzheimer's disease (AD), but their relationships with each other and the impact of their interaction on AD remain to be addressed. Here, we found that amyloid (A)-β treatment downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL) 1 through the hypermethylation of its promoter region in HT22 cells and that the inhibition of DNA methylation ameliorated circadian rhythm disorders and restored BMAL1 protein expression by reversing its hypermethylation in APPswe/PSEN1dE9 (APP/PS1) mice. Critically, increased levels of interleukin (IL)-17A contributed to BMAL1 downregulation through the hypermethylation of its promoter region, thus leading to circadian disruptions in APP/PS1 mice. Moreover, we revealed that the mitogen-activated protein kinase (MAPK) pathway was responsible for IL-17A-induced DNA methyltransferase (DNMT) 1 upregulation. Taken together, we elucidate a new mechanism connecting IL-17A with altered DNA methylation of Bmal1, which results in circadian disturbances in an AD mouse model.