High-Dimensional Single-Cell Analysis Reveals Coordinated Age-Dependent Neuroinflammatory Microglia-T cell Circuits...

Area of Science:

• Neuroimmunology
• Brain Aging
• Vascular Dementia

Background:

• Aging and cerebrovascular pathology contribute to neuroinflammation in vascular dementia (VaD).
• The precise immune mechanisms driving this interplay are not fully understood.

Purpose of the Study:

• To construct a comprehensive brain immune cell atlas in a mouse model of VaD.
• To investigate age-related changes in immune cell populations and their functional states in the brain.

Main Methods:

• Multi-modal high-dimensional imaging, flow cytometry, and split-pool ligation transcriptomic sequencing were employed.
• Microglia, T cells, macrophages, neutrophils, and B cells were profiled across young and aged mice in health and disease.
• Integration of transcriptomics, cell-cell communication, and multiplex imaging was performed.

Main Results:

• A depletion of Ccr7+ naïve T cells and an expansion of Gzmk+ cytotoxic CD8+ effector memory T cells (T_EM) were observed in the aging brain.
• Microglia exhibited a pro-inflammatory shift with enhanced MHC-I to TCR and CD86 to CD28 co-stimulation.
• Strongest signals originated from activated microglia to Gzmk+ CD8+ T_EM cells, suggesting microglia sustain T cell activation in aging brains.

Conclusions:

• Pro-inflammatory microglia and Gzmk+ CD8+ T_EM cells are key drivers of immune brain aging and neuroinflammation in VaD.
• Age-related microglial polarization may perpetuate cytotoxic T cell activity.
• Disrupting these age-related neuroinflammatory cascades presents a potential therapeutic avenue for VaD.