Microglia heterogeneity in vascular dementia pathology

Area of Science:

• Neuroscience
• Immunology
• Neuropathology

Background:

• Microglia display significant heterogeneity in phenotype and function across different brain conditions.
• Vascular dementia (VaD), a common dementia, is characterized by cerebrovascular pathology that induces specific microglial activation states.

Purpose of the Study:

• To review current knowledge of microglial phenotypes in neurological diseases, with a focus on their role in VaD.
• To describe key VaD-associated microglial phenotypes and discuss their molecular drivers.

Main Methods:

• Literature review synthesizing current understanding of microglial phenotypes in neurological disease.
• Focus on microglial contributions to VaD following vascular insults like chronic cerebral hypoperfusion and stroke.
• Description of specific microglial subsets, including ICAM and IPAM microglia, TREM1+-activated microglia, and cytokine-responsive microglia (CRM).

Main Results:

• Identified spatially segregated microglial subsets (ICAM and IPAM) in ischemic territories.
• Described TREM1+-activated microglia in hemorrhagic foci and cytokine-responsive microglia (CRM) in human VaD brains.
• Discussed molecular drivers of microglial heterogeneity, challenging the M1/M2 dichotomy.

Conclusions:

• Microglial heterogeneity in VaD is complex and region-specific, necessitating a move beyond the M1/M2 model.
• Proposed a framework for developing precision immunomodulatory therapies for VaD.
• Highlighted antibody-mediated approaches and in situ cellular reprogramming as potential future interventions for VaD.