Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving synapse dysfunction, neuronal death and disorientation of cognitive processes that are caused by the accumulation of amyloid-β (Aβ) along with aberrant phosphorylation of tau. Aberrant proteolytic processing of amyloid precursor protein (APP) promotes Aβ production, which is pro-oxidant, activates microglia, and promotes chronic neuroinflammation. In parallel, neurofibrillary tangle formation, microtubule destabilisation, and impaired axonal transport are the consequences of pathological tau phosphorylation, which together are associated with accelerated neuronal degeneration. Recent findings implicate epitranscriptomic Dysregulation as an important, but understudied, component of AD pathobiology. In particular, emerging evidence suggests that the expression and activity of METTL3 are dynamically regulated throughout the course of AD, with up- or down-regulation at different disease stages, in specific brain regions, and across cell types, indicating that METTL3 signalling is dysregulated rather than uniformly increased or decreased in AD pathogenesis. Therefore, the changes in m6A deposition mediated by METTL3 could be different in various pathological contexts and cell types, with different downstream consequences in terms of neuronal survival, glial activation and inflammatory signalling. Context-dependent dysregulation of this regulatory axis drives a pronounced elevation in important pro-inflammatory mediators and promotes pyroptosis, including NLRP3, IL-1β, and STAT3, thereby enhancing glial activation, inflammasome assembly and caspase-dependent neuronal death. Integrating the Ab-mediated pathology, tau-mediated cytoskeletal dysfunction and chronic neuroinflammation, the METTL3/IGF2BP2 pathway defines a convergence point that helps break down neuronal homeostasis and plasticity. This review compiles new mechanistic truths of how m⁶A-dependent RNA regulation contributes to the progression of AD and discusses therapeutic opportunities of METTL3/IGF2BP2 axis targeting for novel RNA-based therapies for neurodegenerative disease.