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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The CosMx® SMI and decoder probes are not offered and/or delivered to the Federal Republic of Germany for use in the Federal Republic of Germany for the detection of cellular RNA, messenger RNA, microRNA, ribosomal RNA and any combinations thereof in a method used in fluorescence in situ hybridization for detecting a plurality of analytes in a sample without the consent of the President and Fellows of Harvard College (Harvard Corporation) as owner of the German part of EP 2 794 928 B1. The use for the detection of cellular RNA, messenger RNA, microRNA, ribosomal RNA and any combinations thereof is prohibited without the consent of the President and Fellows of Harvard College (Harvard Corporation).
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