Targeting TREM2 signaling shows limited impact on cerebrovascular calcification

被引:1
作者
Sridhar, Sucheta [1 ,2 ,3 ]
Zhou, Yingyue [4 ]
Ibrahim, Adiljan [5 ]
Bertazzo, Sergio [6 ]
Wyss, Tania [7 ]
Swain, Amanda [4 ]
Maheshwari, Upasana [1 ]
Huang, Sheng-Fu [1 ]
Colonna, Marco [4 ]
Keller, Annika [1 ,2 ,3 ]
机构
[1] Univ Zurich, Univ Hosp Zurich, Clin Neurosci Ctr, Dept Neurosurg, Zurich, Switzerland
[2] Univ Zurich, Neurosci Ctr Zurich, Zurich, Switzerland
[3] Swiss Fed Inst Technol, Zurich, Switzerland
[4] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA
[5] Alector, South San Francisco, CA USA
[6] UCL, Dept Med Phys & Biomed Engn, London, England
[7] Swiss Inst Bioinformat, AGORA Canc Res Ctr, TDS facil, Lausanne, Switzerland
基金
瑞士国家科学基金会;
关键词
BRAIN CALCIFICATIONS; ALZHEIMERS-DISEASE; SIGLEC-H; MICROGLIA; BONE; MUTATIONS; RECEPTOR; GENE; ACTIVATION; EXPRESSION;
D O I
10.26508/lsa.202402796
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 Pdgfbret/ret 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 Pdgfbret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGF beta 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.
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页数:16
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