Targeting TREM2 signaling shows limited impact on cerebrovascular calcification

• Published in: Life science alliance 2025-01, Vol.8 (1), p.e202402796
• Main Authors: Sridhar, Sucheta, Zhou, Yingyue, Ibrahim, Adiljan, Bertazzo, Sergio, Wyss, Tania, Swain, Amanda, Maheshwari, Upasana, Huang, Sheng-Fu, Colonna, Marco, Keller, Annika
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Brain - pathology; Cerebrovascular Disorders - metabolism; Cerebrovascular Disorders - pathology; Disease Models, Animal; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Microglia - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Signal Transduction; Vascular Calcification - metabolism; Vascular Calcification - pathology
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202402796

Brain calcification, the ectopic mineral deposits of calcium phosphate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications.