Oligodendrocyte precursor cell regulates microglial transition to neuroprotective phenotype by BMP4 driven acquisition of disease associated state in Alzheimer's disease

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by cognitive decline and memory loss. Oligodendrocyte precursor cells (OPCs) reciprocally communicate with microglia in a context-dependent manner probably for immune surveillance, extending beyond their initial function as progenitor cells. In this study, we showed that late-OPC, also known as committed oligodendrocyte precursors (COPs), markedly upregulated expression of Bmp4 in response to Amyloid-ß (Aß). Selective Bone morphogenetic protein 4 (Bmp4) knock-out in OPCs of AD mouse model led to impairment of microglial clustering around Aß plaque and Aß phagocytosis, resulting in a substantial increase of Aß deposition alongside dystrophic neurites. Mechanistically, Mothers against decapentaplegic homolog (Smad) signaling pathway, activated by Bmp4 derived from late-OPC, directly induced Triggering receptor expressed on myeloid cells 2 (Trem2) expression in microglia. This molecular cascade was required for robust acquisition of the disease-associated microglia (DAM) transcriptome, ultimately contributing to the development of neuroprotective DAM at early stage of amyloid deposition, prior to severe neuronal loss. Late-OPC sourced Bmp4 dependent appearance of DAM facilitated microglial barrier for Aß plaque compaction, thereby insulating toxic Aß species from adjacent neurites. Notably, intracerebroventricular administration of adeno-associated virus (AAV) carrying Bmp4 to AD mouse enhanced Trem2 expression of microglia around Aß plaque, resulting in acceleration of plaque compaction. Consequently, this intervention alleviated synaptic damage and memory loss. Taken together, our findings strongly suggest that OPC-specific Bmp4 drives a molecular cascade to turn microglia into protective phenotype, providing a theoretical basis for a novel therapeutic strategy to target AD onset. Overall design: To uncover how oligoednrocyte precurosor cells sourced Bmp4 is involved amyloid pathology, we performed Single-cell RNA sequencing (scRNA-seq) of cortex from 5xFAD;PdgfraCreERT2;Bmp4+/+ and 5xFAD;PdgfraCreERT2;Bmp4-/- mice.