Human microglial state dynamics in Alzheimer's disease progression

Area of Science:

• Neuroscience
• Genomics
• Immunology

Background:

• Microglial states significantly impact neuroinflammation and neurodegeneration in diseases like Alzheimer's disease (AD), but their specific roles remain unclear.
• Understanding these states is crucial for developing targeted therapies for neurodegenerative conditions.

Purpose of the Study:

• To comprehensively characterize microglial transcriptional and epigenomic states in human subjects with diverse Alzheimer's disease (AD) pathologies.
• To identify genes and regulatory networks associated with specific microglial states and their dysregulation in AD.
• To investigate the functional consequences of altered microglial states and their relationship with AD risk genes.

Main Methods:

• Single-nucleus RNA sequencing and epigenomic profiling of 194,000 microglia across 443 human subjects.
• Bioinformatic analysis to annotate microglial transcriptional states and identify differentially expressed genes in AD.
• Integration of transcriptomic, epigenomic, and motif data to infer gene regulatory networks and upstream regulators.
• Functional validation using induced pluripotent stem cell (iPSC)-derived microglia-like cells.

Main Results:

• Annotation of 12 distinct microglial transcriptional states, including homeostatic, inflammatory, and lipid-processing states, with specific dysregulation observed in AD.
• Identification of 1,542 differentially expressed genes in microglia associated with AD, showing both state-specific and disease-stage-specific alterations.
• Inference of gene regulatory networks and enhancer-gene links, revealing transcription factor-driven transitions between microglial states.
• Demonstration that manipulating predicted regulators can induce homeostatic features or inhibit inflammation in human microglia-like cells.
• Pinpointing the expression of AD-risk genes within specific microglial states and their altered regulation during AD progression.

Conclusions:

• This study provides an unprecedented high-resolution map of microglial states and their alterations in Alzheimer's disease.
• The findings elucidate the molecular mechanisms underlying microglial state transitions and their contribution to AD pathogenesis.
• The identified regulators and state-specific gene alterations offer potential therapeutic targets for modulating neuroinflammation and neurodegeneration in AD.