Midbrain extracellular matrix and microglia are associated with cognition in aging mice.

Daniel T Gray, Abigail Gutierrez, Yasaman Jami-Alahmadi, Vijaya Pandey, Lin Pan, Ye Zhang, James A Wohlschlegel, Ross A McDevitt, Lindsay M De Biase

Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. [email protected] of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. [email protected]. · pubmed

Paper

Abstract

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. In this study we combine ECM-optimized proteomic workflows with histological analyses in aging mice and discover regional differences in ECM composition and aging-induced ECM remodeling across basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis and identify 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 observations indicate that changing microglia-ECM-synapse interactions contribute to cognitive functioning during healthy aging.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper claims that aging midbrain microglia lose their ability to interact with and regulate the extracellular matrix, which contributes to cognitive decline. This research is relevant as it explores the underlying mechanisms of cognitive aging, focusing on the interactions between microglia, the extracellular matrix, and synapse integrity, which are critical for understanding and potentially addressing the root causes of aging-related cognitive decline.

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