Trem2 deficiency attenuates microglial phagocytosis and autophagic-lysosomal activation in white matter hypoperfusion

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Chronic cerebral hypoperfusion causes demyelination and microglial activation in the central nervous system (CNS).
• Triggering receptor expressed on myeloid cells 2 (Trem2) is crucial for microglial function in CNS disorders.
• The role of Trem2 in chronic cerebral hypoperfusion-induced white matter injury remains unclear.

Purpose of the Study:

• To investigate the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion.
• To elucidate the effects of Trem2 deficiency on microglial responses and white matter integrity.

Main Methods:

• Utilized a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS).
• Analyzed white matter integrity, microglial phagocytosis, and autophagic-lysosomal pathway activation.
• Examined the impact of Trem2 knockout on microglial phenotype and lipid accumulation in vitro.

Main Results:

• Chronic hypoperfusion led to demyelination, increased microglial phagocytosis, and autophagic-lysosomal pathway activation, with elevated Trem2 expression.
• Trem2 knockout attenuated white matter lesions and microglial responses.
• Trem2 deficiency suppressed phagocytosis, reduced autophagic-lysosomal activation, promoted anti-inflammatory/homeostatic microglial phenotypes, and inhibited lipid accumulation.

Conclusions:

• Trem2 plays a significant role in exacerbating microglial phagocytosis and autophagic-lysosomal activation during hypoperfusion-induced white matter injury.
• Targeting Trem2 may offer a therapeutic strategy for treating chronic cerebral hypoperfusion and associated white matter damage.