Single cell profiling reveals GSM-15606 attenuates air pollution-induced inflammation and preserves hippocampal neurogenesis.
Publication Year:
2026
PubMed ID:
41660771
Funding Grants:
Public Summary:
Air pollution is linked to memory loss and dementia, but how it affects individual brain cells remains unclear. Researchers studied mice exposed to diesel exhaust particles, focusing on a brain region important for learning and memory. They found that pollution triggered inflammation in the brain’s immune and support cells, altered stem cells that produce new neurons, and reduced the number of immature neurons. An experimental drug, GSM-15606, reduced many inflammatory responses in immune and support cells but did not reverse the inflammatory changes in neural stem cells. These findings suggest that reducing inflammation could help limit some effects of air pollution on the brain, while additional approaches may be needed to protect the formation of new neurons.
Scientific Abstract:
INTRODUCTION: Air pollution (AirPoll) is a major environmental risk factor for age-related cognitive decline and dementia, yet we poorly understood the cellular and molecular mechanisms underlying its effects and their potential attenuation. METHODS: We combined single cell RNA sequencing with immunohistochemistry to determine transcriptional responses in microglia, astrocytes, neurons and neural stem cells in the hippocampus of mice following exposure to chronic diesel exhaust particle (DEP). Differential gene expression profiles were compared between filtered-air and DEP exposed animals. The gamma secretase modulator GSM-15606 (BPN) was used to probe selective rescue of inflammatory signatures across distinct cell populations. RESULTS: DEP exposure triggered robust inflammatory programs in microglia and astrocytes, including upregulation of cytokine signaling components, innate immune receptors, stress-responsive transcription factors, and markers of reactive glial phenotypes. In neural stem cells, DEP induced activation of gliosis-associated pathways, including Il6st, Stat3, and Txnip, consistent with a pro-inflammatory state that may bias lineage decisions. Immunostaining confirmed a significant reduction in immature neurons in the neurogenic niche after AirPoll exposure. GSM-15606 attenuated many DEP-induced transcriptional alterations in microglia and astrocytes, reducing expression of inflammatory mediators and reactive gliosis markers, but did not modulate the inflammatory profile of neural stem cells. CONCLUSIONS: AirPoll activates divergent inflammatory pathways across hippocampal cell populations and suppresses neurogenesis. Targeting inflammation with GSM-15606 selectively reverses glial but not neural stem cell responses, highlighting cell-type-specific mechanisms and potential therapeutic pathways to mitigate pollution-related cognitive vulnerability. These results support GSM-15606 as a protective agent against AirPoll-induced hippocampal dysfunction and amyloidogenic stress.