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Blood-borne macrophages contribute to Alzheimer's disease modification through a TREM2-independent pathway

ABSTRACT: Microglia and monocyte-derived macrophages (MDM) are key players in coping with Alzheimer's disease (AD). 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 AD via MDM involvement. Blocking PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta (Aβ)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 (e.g. Mrc1, Msr1). Blocking monocytes trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 in Trem2-/-5xFAD mice, and similarly but to lower extent in Trem2+/+5xFAD mice. These results highlight a TREM2-independent disease-modifying activity of MDM in amyloidosis mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE176085 | GEO | 2021/10/24

REPOSITORIES: GEO

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