Increased mA modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress.

N6-methyladenosine (mA) RNA modification is a new epigenetic molecular mechanism involved in various biological or pathological processes. Exposure to aluminum (Al) has been considered to promote neuronal apoptosis resulting in cognitive dysfunction, yet whether mA modification participates in the underlying mechanism remains largely unknown. Here, rats exposed to aluminum-maltolate [Al(mal)] for 90 days showed impaired learning and memory function and elevated apoptosis, which were related to the increased mA level and decreased fat mass and obesity-associated protein (FTO, an mA demethylase) in the hippocampus. Accordingly, similar results presented in PC12 cells following Al(mal) treatment and FTO overexpression relieved the increased apoptosis and mA level in vitro. Next, we identified brain-derived neurotrophic factor (BDNF) as the functional downstream target of FTO in a mA-dependent manner. Furthermore, it was found that as the onset of aluminum neurotoxicity, oxidative stress may be the upstream regulator of FTO in aluminum-induced apoptosis. Taken together, these results suggest that increased mA modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress.