Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis.

Microglia and monocyte-derived macrophages (MDM) are key players in dealing with Alzheimer's disease. In amyloidosis mouse models, activation of microglia was found to be TREM2 dependent. Here, using Trem25xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify Alzheimer's disease via MDM involvement. Blockade of PD-L1 in Trem25xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2 and Trem25xFAD mouse brains, express a unique set of genes encoding scavenger receptors (for example, Mrc1, Msr1). Blockade of monocyte trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 treatment in Trem25xFAD mice and similarly, but to a lesser extent, in Trem25xFAD mice. These results highlight a TREM2-independent, disease-modifying activity of MDM in an amyloidosis mouse model.