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 Trem2^−/−5xFAD 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 Trem2^−/−5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta_1–42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2^−/− and Trem2^+/+5xFAD 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 Trem2^−/−5xFAD mice and similarly, but to a lesser extent, in Trem2^+/+5xFAD mice. These results highlight a TREM2-independent, disease-modifying activity of MDM in an amyloidosis mouse model.