Oligodendrocyte precursor cells-microglia crosstalk via BMP4 drives microglial neuroprotective response and mitigates Alzheimer's disease.

Oligodendrocyte precursor cells (OPCs) rapidly respond to neural injury, becoming activated to preserve myelin homeostasis and interacting with diverse cell types in the central nervous system (CNS). However, the molecular basis of OPC communication with the CNS immune system remains poorly understood. In Alzheimer's disease (AD), microglia respond to amyloid pathology in a neuroprotective manner. Here, we found that Bmp4 produced by late-stage OPCs, termed committed oligodendrocyte precursors (COPs), acts as a critical signal shaping microglial neuroprotective programs in the context of amyloid pathology. OPC-specific genetic ablation of Bmp4 in 5xFAD mice suppressed microglial immune responses and exacerbated amyloid deposition. Single-cell RNA sequencing revealed that Bmp4 deficiency in COPs led to downregulation of disease-associated microglia (DAM) genes in the microglial cluster. Mechanistically, Bmp4-dependent Smad1/5/8 signaling directly regulated Trem2 expression in microglia. Replenishment of Bmp4-expressing COPs in 5xFAD mice enhanced Trem2⁺ DAM acquisition, promoting beneficial barrier formation around Aβ plaques. Similarly, intracerebroventricular (ICV) administration of Sox10 promoter-driven AAV-Bmp4 efficiently ameliorated AD progression. Collectively, these findings uncover an OPC-microglia crosstalk that governs immune surveillance in AD, highlighting COP-targeted enhancement of Bmp4 as a promising avenue for interventions aimed at reinforcing early neuroprotective responses.