Chronic ethanol administration exacerbates memory loss by modification of N6 methyl-adenosine mediated epigenetic signaling

Yuanhang Liao¹Fu Xu¹Yuqing Yan¹Sicheng Zhou^1,2Na Liu²Baomin Dou¹Nivetha Srinivasan¹Weizheng Wang¹Xiongwei Zhu³Jiang Hong Ye¹Ying Xu^1*

• ¹Rutgers University, Newark, Newark, United States
• ²Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, United States
• ³Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States

Background: Chronic alcohol use disorder (AUD) is recognized as one of the most critical risk factors for the progression of Alzheimer's disease (AD). Epigenetic and neuroimmune alterations are closely associated with the development of memory impairment related to AUD and AD.Methods: Adult APP/PS1 transgenic mice received intermittently intraperitoneal injections of ethanol (EtOH, 2.5 g/kg, i.p.) or vehicle with two "drug" treatment days, and one and two "drug-free" days every 7 days for 10 weeks. The novel object recognition (NOR) and Y-maze tests were performed to determine whether chronic ethanol treatment exacerbated memory impairment in these mice. The brain tissues were collected for pathological changes through MeRIP / RNA-sequence analyses and molecular biological assays.The results suggested that chronic intermittent ethanol (CIE) treatment for 10 weeks exacerbated sporadic and spatial memory deficits in NOR and Y-maze tests in the APP/PS1 mice. The pathological assays revealed that CIE procedure increased Aβ plaque burden in the brain of the AD mice, which were consistent with memory behavioral deficits. The subsequent MeRIP /RNA sequence analyses showed that two genes, e.g. Rbm15b and Hnrnpa2b1, were related to N6-methyladenosine (m 6 A) methylation that plays an important role in the development of memory loss.These results were further supported by molecular biological and mRNA-microRNA-lncRNA ceRNA network analyses that demonstrated that the increased Rbm15b and decreased Hnrnpa2b1 were involved in synaptic dysfunction and neuroinflammation in CIE-induced memory impairment in these AD mice.The conclusion drawn is that m 6 A mediated epigenetic dysfunction and immune cells infiltration participate in chronic alcohol use disorder related memory loss in AD mice.