Targeting TREM2 signaling shows limited impact on cerebrovascular calcification

Area of Science:

• Neuroscience
• Immunology
• Radiology

Background:

• Brain calcification involves ectopic calcium phosphate deposits, a key diagnostic marker for primary familial brain calcification.
• Microglia, via triggering receptor expressed in myeloid 2 (TREM2), were previously shown to limit small vessel calcification growth in the Pdgfb mouse model.
• TREM2-activating antibodies have shown promise in clearing pathologies in other diseases, suggesting potential therapeutic applications.

Purpose of the Study:

• To investigate if TREM2-activating antibody administration could mitigate vascular calcification in the Pdgfb mouse model.
• To analyze the effect of TREM2 activation on microglial phenotype and function in the context of brain calcification.

Main Methods:

• Single-nucleus RNA-sequencing to characterize calcification-associated microglia.
• Administration of a TREM2-activating antibody to Pdgfb mice.
• Assessment of calcification load, mineral composition, and microglial phenotype.

Main Results:

• Calcification-associated microglia displayed transcriptional similarities to disease-associated microglia with activated TREM2 and TGFβ signaling.
• TREM2 antibody administration increased cathepsin K deposition by microglia onto calcifications.
• Despite increased cathepsin K, the antibody did not reduce calcification load or alter mineral composition and microglial phenotype.

Conclusions:

• Targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications in this model.
• The study highlights limitations of TREM2 antibody therapy for vascular calcification in primary familial brain calcification.