Methyltransferase-like 14 alleviates neuronal ferroptosis in Alzheimer’s disease by regulating the peroxiredoxin 6/apoptosis signal-regulating kinase 1 signaling pathway
Minghui Zheng, Bingxu Hou, Ruxue Ma, Zheng TanBackground
Alzheimer’s disease is a neurodegenerative disorder, in which ferroptosis contributes to its pathogenesis and progression. This study explored the precise mechanisms of ferroptosis in the pathological development of Alzheimer’s disease.
Methods
Amyloid beta 1–42 oligomer-treated SH-SY5Y cells were used to simulate Alzheimer’s disease
Results
METTL14 levels were decreased in the serum of Alzheimer’s disease patients and in an in-vitro model of Alzheimer’s disease, and serum levels correlated with the degree of cognitive impairment. METTL14 overexpression significantly inhibited amyloid beta 1–42 oligomer-induced ferroptosis and cytotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification increased PRDX6 mRNA stability, which inactivated the ROS–apoptosis signal-regulating kinase 1/p38 pathway. Rescue experiments demonstrated that PRDX6 overexpression reversed sh-METTL14-induced ferroptosis and neurotoxicity.
Conclusion
METTL14 suppressed neuronal ferroptosis to delay Alzheimer’s disease progression through m6A modification of PRDX6 to inactivate the ROS–apoptosis signal-regulating kinase 1/p38 pathway. Our observations provide a potential therapeutic strategy for Alzheimer’s disease.