INTEGRATIVE ANALYSIS OF MICROGLIAL SINGLE-CELL TRANSCRIPTOMES IN AD MOUSE MODELS AND HUMAN DISEASE

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive cognitive decline, accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. Microglia, the resident immune cells of the brain, are essential for maintaining neural homeostasis through environmental surveillance, clearance of extracellular protein aggregates, and regulation of inflammatory responses. Recent evidence indicates that mutations in microglia-associated genes can profoundly impact AD progression by disrupting key functions such as lipid metabolism and phagocytic activity. These dysfunctions contribute to increased neuroinflammation and impaired Aβ clearance, thereby exacerbating disease pathology.
Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) have revealed unprecedented microglial heterogeneity in both amyloidosis AD mouse models and human AD brains. However, inconsistencies in nomenclature, variability in identified microglial subtypes, and species-specific differences have hindered the establishment of a unified framework for microglial states in AD. In this study, we performed a meta-analysis of publicly available sc/snRNA-seq datasets to identify conserved and divergent microglial transcriptional signatures across AD mouse models and human AD brains. By integrating multiple datasets, we aim to refine microglial classification and distinguish shared versus species-specific microglial populations implicated in AD pathogenesis.