RT Journal Article
SR Electronic
T1 Targeting TREM2 signaling shows limited impact on cerebrovascular calcification
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402796
DO 10.26508/lsa.202402796
VO 8
IS 1
A1 Sridhar, Sucheta
A1 Zhou, Yingyue
A1 Ibrahim, Adiljan
A1 Bertazzo, Sergio
A1 Wyss, Tania
A1 Swain, Amanda
A1 Maheshwari, Upasana
A1 Huang, Sheng-Fu
A1 Colonna, Marco
A1 Keller, Annika
YR 2025
UL https://www.life-science-alliance.org/content/8/1/e202402796.abstract
AB 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 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.The snRNA-seq data consisting of fastq raw data files and outputs from CellRanger v. 5.0.1. pipeline have been deposited in the Gene Expression Omnibus (GEO) database with the accession number GSE263392. Gene expression lists and supporting data values have been provided within the article. Additional data related to this article may be requested from the authors.