Objective: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).
Methods: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.
Results: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.
Conclusion: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.
Keywords: Alzheimer’s disease; METTL3; TIGAR; m6A; microglia polarization.
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