TREM2-Mediated Microglial Regulation of Oligodendrocyte Precursor Cell Maturation for Connectome Repair

This hypothesis proposes that microglial TREM2 activation serves as a master regulator that coordinates both synaptic pruning and oligodendrocyte precursor cell (OPC) maturation to restore structural connectome integrity. TREM2-activated microglia would function as central orchestrators, using their synaptic pruning machinery to identify damaged or dysfunctional neural circuits while simultaneously releasing specific trophic factors and cytokines that promote OPC differentiation into mature oligodendrocytes at sites of identified damage. The mechanism involves TREM2 signaling cascades that enhance microglial phagocytic capacity for clearing synaptic debris and myelin fragments, while triggering the release of pro-myelination factors such as IGF-1, PDGF-AA, and specific extracellular matrix proteins. This dual-function approach leverages the spatial precision of microglial synaptic surveillance to target OPC activation specifically where structural connectivity has been compromised. The activated microglia would create localized microenvironments that favor OPC recruitment, proliferation, and differentiation into myelinating oligodendrocytes, effectively coupling the destruction of damaged connections with the reconstruction of healthy myelin sheaths. This coordinated response would be particularly relevant in neurodegenerative diseases, traumatic brain injury, and aging-related cognitive decline where both synaptic dysfunction and white matter degradation occur simultaneously. The hypothesis predicts that TREM2 enhancement would result in improved structural connectome metrics, enhanced white matter integrity on DTI imaging, and restored cognitive function through the coordinated repair of both synaptic and myelination deficits.