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

Raz Dvir-Szternfeld, Giulia Castellani, Michal Arad, Liora Cahalon, Sarah Phoebeluc Colaiuta, Hadas Keren-Shaul, Tommaso Croese, Chiara Burgaletto, Kuti Baruch, Tyler Ulland, Marco Colonna, Assaf Weiner, Ido Amit, Michal Schwartz

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 beta1–42 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.

Original languageEnglish
Pages (from-to)60-73
Number of pages14
JournalNature Aging
Volume2
Issue number1
DOIs
StatePublished - Jan 2022

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