Co-regulation of microglial subgroups in Alzheimer’s amyloid pathology: Implications for diagnosis and drug development

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Neuroinflammation drives AD progression and therefore represents a promising target for diagnosis and therapy. In early AD, microglia polarize into pro-inflammatory and anti-inflammatory cellular subgroups that mediate the initial immune response, yet the regulatory relationships between these microglial subgroups remain poorly understood. In this study, we investigated the interplay between pro- and anti-inflammatory microglial subgroups from multiple perspectives. Comparative transcriptomics and bioinformatics analyses implicated the Trem2 signaling pathway in an anti-inflammatory microglial subgroup. Fluorescence-activated cell sorting (FACS) and gene regulation analysis indicated that microglial subgrouping and microgliosis preceded cytokine upregulation during early amyloid pathology. Further immunoassays revealed that anti-inflammatory Neurodegeneration-Related Modules and pro-inflammatory microglial subgroups, Interferon-Related Modules and LPS-Related Modules, were co-regulated by shared upstream pro-inflammatory regulators. Such co-regulation of heterogeneous microglial subgroups may balance microglial activation and promote the development of AD chronic neuroinflammation. In summary, our study uncovered previously overlooked co-regulation of microglial subgroups in AD and provides a systems biology framework that may inform improved diagnostic markers and immunotherapeutic strategies.