Electroacupuncture reduces amyloid beta accumulation and improves cerebral ischemia-induced cognitive impairment in a N6-methyladenosine-dependent manner.

Electroacupuncture (EA) has been widely used in the clinical treatment of cognitive impairment after cerebral ischemia (CI) in China, but the specific molecular mechanism is not fully understood yet. In this study, permanent middle cerebral artery occlusion (pMCAO) model mice were administrated with EA therapy, Morris water maze (MWM) test was used for evaluation of cognitive function, Nissl staining was employed to quantify surviving neurons in the hippocampus, and enzyme-linked immunosorbent assay (ELISA) was utilized to detect the levels of amyloid beta (Aβ). The results showed that EA treatment obviously improved learning and memory abilities in the mice with pMCAO, inhibited neuronal loss in the hippocampus, and reduced the levels of Aβ40 and Aβ42. Meanwhile, we observed that METTL3 expression and total N6-methyladenosine (m6A) levels were significantly increased in the hippocampal tissues of pMCAO mice, which were reduced by EA therapy. Then, hippocampal neuronal cell line HT22 was induced by oxygen-glucose deprivation (OGD) to verify the molecular regulatory mechanism in vitro, and we found that METTL3 upregulated BACE1 expression in OGD-induced HT22 cells through promoting m6A enrichment on BACE1 mRNA, thus facilitating Aβ production and cell apoptosis of OGD-induced HT22 cells. Finally, through in vivo functional recovery experiments, we demonstrated that EA therapy restrained the METTL3/BACE1 axis to alleviate Aβ accumulation and cognitive dysfunction in pMCAO model mice. In summary, our data reveals that the m6A-modified BACE1 pathway is one of the molecular targeting mechanisms for EA treatment in cognitive impairment after CI.