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Precise Brain Mapping to Perform Repetitive In Vivo Imaging of Neuro-Immune Dynamics in Mice
Published on: August 7, 2020
Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white
Chase M Carver1,2, Paul T Gomez1,2, Sonia L Rodriguez1,2
1Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Abstract:
Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.
Insights
Aging brain white matter shows a unique microglial state characterized by senescence and disease-associated microglia (DAM) markers, including galectin-3. Senotherapeutic interventions partially reversed this proinflammatory state in aged mice.
Area of Science:
- Neuroscience
- Aging Research
- Cellular Biology
Background:
- Brain white matter changes are linked to cognitive decline in late life.
- The cellular and molecular mechanisms behind white matter vulnerability in aging are not fully understood.
Purpose of the Study:
- To investigate the cellular and molecular characteristics of aged brain white matter microglia.
- To identify specific microglial phenotypes and their role in white matter aging.
- To explore potential therapeutic interventions targeting these microglial states.
Main Methods:
- Utilized naturally aged mice for study.
- Employed regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling, and CosMx spatial molecular imaging.
- Conducted single-cell spatial trajectory analyses.
- Applied pharmacogenetic and pharmacological senotherapeutic interventions.
Main Results:
- Identified a distinct microglial population in aged white matter (hippocampal-adjacent, fimbria) co-expressing disease-associated microglia (DAM) and senescence (SenBrain) gene signatures, including galectin-3 (GAL3/Lgals3).
- Spatial trajectory analyses suggested complex cell fate transitions leading to this aged microglial state.
- Senotherapeutic treatments reduced GAL3+ DAM abundance and promoted a more youthful microglial organization in aged fimbria.
Conclusions:
- Aged brain white matter harbors a unique, proinflammatory microglial state enriched in senescence and DAM markers.
- This microglial phenotype is partially reversible through senotherapeutic interventions.
- These findings highlight a novel cellular mechanism contributing to white matter aging and cognitive decline.
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