Senescent and disease-associated microglia are modifiable features of aged brain white matter


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Aged brain white matter tracts undergo structural and functional changes associated with cognitive decline, but the cell fates and mechanisms that confer selective vulnerability are not well defined. We discovered that senescent and disease-associated microglial (DAM) phenotypes converge in fimbria and corpus collosum white matter regions of aged mice. Through GeoMx Digital Spatial Profiling, CosMx Spatial Molecular Imaging, and gold standard methods, we identified microglia in aged white matter characterized by altered morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and Cdkn2a/p16ink4a, among other cyclin-dependent kinase inhibitors. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM cell frequency and rejuvenated microglial identity in the fimbria of aged female mice. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic interventions to promote homeostatic maintenance in the aged brain.

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Marissa Schafer, PhD

Associate Professor Senior Associate Consultant II, Department of Physiology and Biomedical Engineering Department of Neurology, Director of the Brain and Systemic Aging Laboratory at Mayo Clinic