TREM2 Agonism Affects Human Microglia Response in the Presence of Amyloid Pathology In Vivo

Abstract

AbstractBackgroundPharmacological activation of TREM2 represents a novel therapeutic approach to slow Alzheimer´s disease (AD) progression. Mutations in microglial gene, TREM2, confers increased risk to developing late‐onset AD. Moreover, animal studies demonstrate the loss‐of‐of function variants or complete absence of Trem2 aggravates amyloid pathology. Genetic ablation of TREM2 function has been shown to lock microglia in a homeostatic state, preventing a switch to the disease‐associated state supporting the phagocytic clearance of misfolded proteins and cellular debris. Due to low gene sequence and protein structure homology between mouse and human TREM2, as well as phenotypical disparities between mouse and human microglia, monitoring the impact of TREM2 activation in vivo requires humanized animal models.MethodHere we studied the impact of TREM2 agonism on xenografted human microglia in a mouse model of amyloid pathology. We systematically treated 7‐month‐old transgenic AppNL‐G‐F mice transplanted with human embryonic‐stem‐cell‐derived microglia with TREM2 small molecule agonists. Human microglia were sorted from the brain and subsequently assessed using multi‐omics technologies.ResultThe activation of TREM2 lead to increased expression of cytokines and chemokines in xenografted human microglia in the presence of amyloid pathology in AppNL‐G‐F, but not in wild‐type mice. Other changes in the transcriptome profile indicated shifts in microglia populations in TREM2‐agonist‐treated AppNL‐G‐F mice. These effects were observed at exposures consistent with activation of TREM2 in vitro assessed by pSYK and sTREM2 levels.ConclusionAll together, we show the human microglia xenograft mouse model is a valuable tool to study the impact of pharmacological TREM2 activation in the presence of AD neuropathology.