THE MIR-29 FAMILY AS POTENTIAL MEDIATORS OF MICROGLIAL ADAPTATION TO RESISTANCE TRAINING IN THE MOUSE BRAIN

Chronic microglia-driven neuroinflammation is a hallmark of Alzheimer's disease (AD). Under chronic stress, like Aβ accumulation, microglia often shift from neuroprotective to detrimental phenotypes. The miR-29 family modulates both immune activation and amyloidogenic pathways by targeting IFNγ, TNFα, and BACE1. Given that miR-29 is downregulated in AD patient’s brain tissue, we investigated its role in regulating microglial adaptation to lifestyle interventions, specifically resistance training, taking advantage of the systemic miR-29a/b1 knockout (KO) mouse model. Wild-type (WT) and KO mice underwent a 4-week endurance (END) or resistance (RES) training (N= 8/genotype/group). Regional expression of miR-29 family members, exercise-associated miRNAs, and IL-1β mRNA was quantified by qPCR. Microglial density and morphology were evaluated by Iba1 immunohistochemistry and fractal dimension in cerebral cortex, striatum, and cerebellum in a subgroup (N= 3/genotype/group).
In WT mice, miR-29a-3p was predominantly expressed in cerebral cortex, and its absence selectively modified exercise-associated miRNAs expression in this region. Hippocampal IL-1β expression increased after RES in both genotypes. In WT mice, RES promoted more compact and highly branched microglia in the cortex, indicating a resilient adaptive response. In contrast, RES KO mice showed a striking lack of microglial immunolabeling both in cortex and striatum, a pattern not observed in END KO mice. Our findings suggest that miR29a/b1 cluster appears critical for healthy microglial remodeling. Its absence may render resistant training detrimental, potentially triggering apoptotic pathways or an exaggerated proinflammatory state. These results underscore the necessity of a finely regulated miRNA-mediated inflammatory response for effective microglial function and brain resilience.