Increased m 6 A modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress.

N6-methyladenosine (m6 A) 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 m6 A modification participates in the underlying mechanism remains largely unknown. Here, rats exposed to aluminum-maltolate [Al(mal)3 ] for 90 days showed impaired learning and memory function and elevated apoptosis, which were related to the increased m6 A level and decreased fat mass and obesity-associated protein (FTO, an m6 A demethylase) in the hippocampus. Accordingly, similar results presented in PC12 cells following Al(mal)3 treatment and FTO overexpression relieved the increased apoptosis and m6 A level in vitro. Next, we identified brain-derived neurotrophic factor (BDNF) as the functional downstream target of FTO in a m6 A-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 m6 A modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress.