METTL3/IGF2BP1 Axis Orchestrates m6A-Dependent NCAM1 Preservation to Combat Age-Related Cognitive Decline
TL;DR
An m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging is established, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.
Abstract
Highlights What are the main findings? Hippocampal Ncam1 exhibits reduced m6A methylation and down-regulated expression in aged SAMP8 mice. METTL3-mediated m6A modification stabilizes Ncam1 mRNA via the reader protein IGF2BP1. Overexpression of METTL3/IGF2BP1-NCAM1 axis alleviates neuronal senescence and rescues age-related learning-memory deficits. What is the implication of the main finding? This work defines a new epitranscriptomic regulatory axis for hippocampal aging and cognitive impairment. It links m6A RNA modification to synaptic plasticity maintenance in the aging brain. METTL3-IGF2BP1-NCAM1 may serve as potential targets for treating age-associated cognitive decline. Abstract Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its “writers,” “erasers,” and “readers,” yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.