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

ABSTRACT: 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-β (Aβ). Selective Bone morphogenetic protein 4 (Bmp4) knock-out in OPCs of AD mouse model led to impairment of microglial clustering around Aβ plaque and Aβ phagocytosis, resulting in a substantial increase of Aβ 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 Aβ plaque compaction, thereby insulating toxic Aβ species from adjacent neurites. Notably, intracerebroventricular administration of adeno-associated virus (AAV) carrying Bmp4 to AD mouse enhanced Trem2 expression of microglia around Aβ 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE241211 | GEO | 2026/01/20

REPOSITORIES: GEO

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Project description:Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer’s disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or ‘neuroinflammatory-like’ stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.

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

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