Co-regulations of Microglial Subgroups in Alzheimer's Amyloid Pathology: Implications for Diagnosis and Drug Developments

Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Neuroinflammation drives AD disorders and, therefore, is a promising target for diagnosis and drugs. At the early stage of AD, microglia are activated into pro-inflammatory and anti-inflammatory cellular subgroups. These mediate the early immune response in AD neuroinflammation. However, the immune regulations of the microglial subgroups are still largely unknown. In this study, we investigated the relationship between the pro-inflammatory and anti-inflammatory microglial subgroups from multiple angles. Firstly, we constructed immune regulation networks of human AD risk factors and microglial subgroup markers by bioinformatics data mining. Secondly, we performed a comparative transcriptomics analysis between Major Depression Disorder (MDD) acute neuroinflammation and AD chronic neuroinflammation to figure out the immune properties of the AD microglial subgroups. Thirdly, we developed an innovative method of pharmaceutical activating and blocking immunoassays to verify the co-regulations of the AD microglial subgroups. As shown in the result, the human AD risk factors were closely related to microglial subgroups at the level of immune regulation. The comparative transcriptomics confirmed that the Trem2 signaling pathway mediated the major anti-inflammatory microglial subgroup in AD chronic neuroinflammation. The immunoassays revealed that both the anti-inflammatory Neurodegeneration-Related Modules and the pro-inflammatory microglial subgroups, Interferon-Related Modules and LPS-Related Modules, can be co-regulated by common upstream pro-inflammatory regulators. The co-regulations of the heterogeneous microglial subgroups balanced microglial activations. This balance may contribute to the formation of AD chronic neuroinflammation. In brief, these new findings show the double-edged role of microglial activations, which will help us to improve diagnostic markers and immune therapy from the perspectives of systematic biology and network pharmacology.