Riprogrammazione metabolica e modulazione della microglia nella sclerosi laterale amiotrofica (SLA)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, in which neuroinflammation and microglial activation play a central role. This study investigated the spatial and temporal dynamics of microglial activation in the SOD1G93A mouse model, focusing on the motor cortex, striatum, and spinal cord, and evaluated the effects of the metabolic modulator trimetazidine (TMZ). A robust and progressive microglial activation was observed in the spinal cord, accompanied by morphological changes and early upregulation of pro-inflammatory and microglia-associated genes. The simultaneous increase of homeostatic and disease-associated microglia (DAM) markers suggests an activation pattern that does not fully follow the canonical Trem2-ApoE pathway. In contrast, brain microglial alterations were milder, more dynamic, and region-dependent. TMZ partially reduced microglial activation in the spinal cord, preserving a more ramified morphology and decreasing inflammatory gene expression. Complementary studies in zebrafish and skeletal muscle cells also showed beneficial effects on locomotor performance, motor neuron activity, and myofiber maturation. Finally, serotonergic modulation revealed a complex, context-dependent role in neuroinflammation. Overall, these findings highlight the complexity of microglial responses in ALS and support targeting metabolic and neuroimmune pathways as potential therapeutic strategies.