Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease
Daniel C. Ellwanger, Shoutang Wang, Simone Brioschi, Zhifei Shao, Lydia Green, Ryan Case, Daniel Yoo, Dawn Weishuhn, Palaniswami Rathanaswami, Jodi Bradley, Sara Rao, Diana Cha, Peng Luan, Shilpa Sambashivan, Susan Gilfillan, Samuel A. Hasson, Ian N. Foltz, Menno van Lookeren Campagne, Marco Colonna
Abstract
Significance Alzheimer’s disease (AD) is the most common dementia; no therapy halts its progression. AD pathology, including amyloid-β (Aβ) plaques, neurofibrillary tangles, and synapse loss, triggers microglial responses that modulate disease course. The TREM2 receptor promotes microglia responses to pathology and a variant, TREM2 R47H , impairs ligand binding and increases AD risk. Employing scRNA-seq, we asked: can an anti-TREM2 antibody, acting as a surrogate ligand, stimulate microglia in mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 CV ) or TREM2 R47H ? One systemic injection of anti-TREM2 restored microglia activation in TREM2 R47H mice but promoted limited activation in mice carrying TREM2 CV , which binds endogenous ligands. Thus, anti-TREM2 can strengthen microglial responses during AD, contingent on preexisting TREM2 engagement and basal activation.