Extracellular matrix remodeling during aging aligns with synapse, microglia, and cognitive status

Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. Using ECM-optimized proteomic workflows and histological analyses, we discovered striking regional differences in ECM composition and aging-induced ECM remodeling across key basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis to identify robust relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these foundational observations implicate changing microglia-ECM-synapse interactions as a key determinant of cognitive functioning during healthy aging.