TREM2‐independent neuroprotection is mediated by monocyte‐derived macrophages in a mouse model of Alzheimer’s disease

Background The relative contributions of microglia and infiltrating monocyte‐derived macrophages (MDMs) to containing Alzheimer’s disease (AD) are not fully understood. In the 5xFAD animal model of amyloidosis, disease‐associated microglia (DAM) expressing the Triggering receptor expressed on myeloid cells 2 (TREM2), are found in close proximity to amyloid beta (Aβ) plaques. Deletion of TREM2 results in the absence of DAM and in an increased Aβ‐plaque load. However, the necessity of TREM2 and DAM for resolving AD pathology is still debatable. Method Here, we activated systemic immunity by blocking the programmed cell death protein 1 / ligand (PD‐1/PD‐L1) pathway in TREM2‐/‐ and TREM2+/+ 5xFAD mice, to decipher the roles of the different myeloid populations in mitigating AD pathology. Result We found that anti‐PD‐L1 treatment resulted in cognitive improvement in TREM2‐/‐ and TREM2+/+ 5xFAD mice. In addition, in both TREM2‐/‐5xFAD and TREM2+/+5xFAD, the treatment resulted in a reduction in water soluble‐Aβ, while reduction of insoluble‐Aβ was observed only in TREM2+/+5xFAD mice. Eliminating monocytes using anti‐CCR2 antibody fully abrogated the observed effects of anti‐PD‐L1 treatment in TREM‐/‐5xFAD mice, and partially eliminated the effects in the TREM2+/+5xFAD. Single‐cell RNA‐seq of myeloid cells isolated from TREM2‐/‐5xFAD brains revealed that MDMs express unique scavenger receptors, previously linked to soluble‐Aβ removal, such as Macrophage scavenger receptor 1 (MSR1). Conclusion Overall, our findings highlight a novel TREM2‐independent pathway by which cognitive improvement and removal of soluble‐Aβ are achieved in an amyloidosis model. Thus, our results support the potential of MDM‐harnessing immunotherapy in treating AD patients, irrespective of whether they carry a TREM2 mutation.