ALKBH5-mediated m6A demethylation of PRMT6 inhibits neuronal apoptosis and ferroptosis in Alzheimer's disease via reducing transcription of ACSL4

Protein arginine methyltransferase 6 (PRMT6) is confirmed to regulate Alzheimer's disease (AD) process. Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis is involved in regulating AD progression. However, whether PRMT6 regulates AD progression through ACSL4-mediated ferroptosis is unknown. AD mice were injected with adeno-associated virus to explore the role of PRMT6 and AlkB homologue 5 (ALKBH5) in vivo. Neuronal cells were treated with amyloid-β protein fragment 1—42 (Aβ1—42) to mimic AD cell models. The expression levels of PRMT6, ALKBH5, ACSL4, GPX4, and SLC7A11 were tested by qRT-PCR or western blot. Cell viability and apoptosis were detected by CCK8 assay and TUNEL staining. The levels of ROS, MDA, SOD and Fe2+ were tested to evaluate ferroptosis. Mouse behavior, neuron injury, Aβ deposition, and neuronal cell apoptosis were examined by morris water maze test, novel object recognition test, histological staining and TUNEL staining. The interactions between PRMT6 and ALKBH5 or ACSL4 were analyzed. PRMT6 expression was upregulated in AD mice. Silencing of PRMT6 repressed Aβ1—42-induced neuronal cell apoptosis and ferroptosis, as well as alleviated cognitive deficits in AD mice. ALKBH5 reduced PRMT6 expression by inhibiting its m6A modification. ALKBH5 overexpression suppressed Aβ1—42 induced apoptosis and ferroptosis in neuronal cells, and this effect was reversed by PRMT6 upregulation. Besides, PRMT6 promoted ACSL4 expression via increasing H3R2me2a on the ACSL4 promoter, and ACSL4 overexpression also abolished the inhibitory effect of PRMT6 knockdown on Aβ1—42-induced cell ferroptosis. Meanwhile, ALKBH5 inhibited neuronal cell ferroptosis to relieve cognitive deficits in AD mice via repressing the PRMT6/ACSL4 axis. ALKBH5 could inhibit neuronal cell ferroptosis to alleviate the progression of AD by decreasing PRMT6-mediated ACSL4 transcription through H3R2me2a. 1. PRMT6 knockdown suppresses Aβ1—42-induced ferroptosis in nerve cells and alleviates cognitive deficits in AD mice; 2. ALKBH5 reduces PRMT6 expression by inhibiting its m6A modification; 3. PRMT6 promotes ACSL4 expression via H3R2me2a modification; 4. ALKBH5 inactivates the PRMT6/ACSL4 axis to alleviate neuronal ferroptosis and relieve cognitive deficits of AD mice.