Related Experiment Video
Updated: Aug 1, 2025
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse
Raz Dvir-Szternfeld1,2, Giulia Castellani1, Michal Arad1
1Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
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.
Insights
Monocyte-derived macrophages (MDM) improve cognition in Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia and monocyte-derived macrophages (MDM) are crucial in Alzheimer's disease (AD) pathogenesis.
- Microglial activation in AD models is often TREM2-dependent.
- The role of MDM in AD, particularly concerning TREM2, requires further elucidation.
Purpose of the Study:
- To investigate if MDM exert their effects through a TREM2-dependent pathway in AD.
- To evaluate the impact of targeting the PD-L1 immune checkpoint on AD pathology and cognition in a TREM2-deficient model.
Main Methods:
- Utilized Trem2 knockout (Trem2-/-) 5xFAD mice, an AD amyloidosis model.
- Administered anti-PD-L1 treatment and assessed cognitive function and amyloid-beta levels.
- Employed single-cell RNA sequencing to analyze MDM gene expression.
- Investigated monocyte trafficking using anti-CCR2 antibody blockade.
Main Results:
- Anti-PD-L1 treatment improved cognition and reduced soluble amyloid-beta in Trem2-/- 5xFAD mice, without altering plaque load.
- MDM from both Trem2-/- and Trem2+/+ 5xFAD mice expressed unique scavenger receptor genes.
- Anti-CCR2 blockade abolished the cognitive benefits of anti-PD-L1 treatment in Trem2-/- 5xFAD mice, and partially in Trem2+/+ 5xFAD mice.
Conclusions:
- MDM demonstrate TREM2-independent, disease-modifying activity in this AD mouse model.
- Targeting PD-L1 offers a potential therapeutic strategy for AD by modulating MDM function.
- Monocyte trafficking is critical for the therapeutic efficacy of anti-PD-L1 treatment in AD.
