Sex-Specific Molecular Architecture of Microglia-Mediated Neuronal Pruning Across the Human Lifespan

Sex-specific differences in neurodegenerative disease susceptibility suggest distinct molecular mechanisms underlying brain aging between males and females. In this study, we investigated transcriptomic profiles of complement system components, microglial markers, and astrocyte/neuronal proteins across the lifespan to elucidate sex-dependent synaptic pruning mechanisms. Comprehensive transcriptomic analysis was performed on brain tissue samples spanning multiple age groups and regions, examining expression patterns of complement genes (C1QA, C1QB, C1QC, C1R, C1S, C3, ITGAM, ITGB2), microglial markers (TMEM119, P2RY12, CSF1R, NLRP3, TREM2, AIF1), and astrocytic, neuronal, and tissue markers (MAP2, SYP, SNAP25, MAPT, GFAP, CHI3L1). Complement system components demonstrated pronounced sex bias. Males exhibited distinct U-shaped age-related patterns, with middle-late childhood (MLC) consistently showing the highest expression for most genes, decreasing in middle age, followed by partial reactivation in nonagenarians, and then a further reduction in centenarians. An oscillatory trajectory across the lifespan was observed in females, with a peak in centenarians. Regional analysis revealed diencephalic predominance and occipital suppression patterns. Microglial activation markers exhibited complex sex-dependent patterns, with males showing higher expression during childhood/adolescence and females demonstrating an elevation in advanced age. These genes displayed limbic and diencephalic enrichment with cerebellar reduction. Neuronal/astrocytic markers showed opposing trajectories: neuronal markers (MAP2, SNAP25, SYP, MAPT) generally declined with age, while astrocytic markers (GFAP, CHI3L1) increased. Males demonstrated compartmentalized gene clustering, while females showed integrated neuro-microglial networks. Functional enrichment analysis confirmed these networks coordinate complement-mediated synapse pruning, representing systematic age-related synaptic remodeling mechanisms that differ fundamentally between sexes and may influence neurodegenerative susceptibility patterns. These findings demonstrate that female brains maintain heightened complement-mediated synaptic pruning throughout aging, representing a double-edged mechanism that may confer adaptive plasticity while increasing vulnerability to neurodegeneration. Male brains exhibit more stable neuronal environments with reduced glial activation, potentially underlying sex-specific trajectories in brain aging and neurodegenerative disease susceptibility.