Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia
Year: 2025
Type: article
Abstract: BACKGROUND: Microglia, the brain’s resident immune cells, play a pivotal role in Alzheimer’s disease (AD) pathogenesis. These cells exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and characterizing these states is essential for understanding AD mechanisms. METHODS: We integrated single-cell and spatial transcriptomic datasets from multiple cohorts and brain regions, encompassing both experimental models and human tissues. Findings were validated through immunostaining of human brain samples. RESULTS: Our comprehensive atlas revealed pronounced heterogeneity among microglial states, with disease-associated microglia (DAM) significantly enriched in AD brains compared to controls. Spatial transcriptomics and immunohistochemistry demonstrated that DAM predominantly localize to external cortical layers and near amyloid plaques, whereas homeostatic microglia are more abundant in internal cortical layers and distal regions. Immunofluorescence staining for P2RY12 and CD68 confirmed these spatial distributions. CONCLUSION: By harmonizing single-cell and spatial transcriptomics, we provide a detailed atlas of microglial diversity, highlighting regional and pathological specificity of microglial states in AD. SIGNIFICANCE: This work advances prior studies by mapping microglial transcriptional states across multiple human cohorts and experimental contexts, integrating spatial data to reveal novel anatomical patterns. The enrichment of DAM in external cortical layers and homeostatic microglia in internal layers represents a previously unreported finding with potential therapeutic implications. While not exhaustive of all microglial datasets, this study establishes the first integrated reference combining single-nucleus and spatial transcriptomics, underscoring the importance of linking microglial diversity to AD neuropathology and brain architecture.
Source: Alzheimer s Research & Therapy
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
Awards: Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, G266544023, G2979291705, G3478357739, G3743240706, Pathway discovery, validation and compound identification for Alzheimer's disease, G4841226479, Risk Factors, Pathology, and Clinical Expressions of AD, Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw, G71004700, G7358292396, G828200374, Elucidating changes in astrocyte subpopulations associated with resistance to Alzheimers Disease pathology in multi-ethnic cohorts, Deconstructing and modeling the single cell architecture of the Alzheimer brain, MENDELIAN RANDOMIZATION FOR UNBIAS BIOMARKER DISCOVERY FOR AD AND OTHER COMPLEX TRAITS, G9000232890, Investigating the Functional Impact of AD Risk Genes on Neuro-Vascular Interactions, G983864884
OpenAlex ID: W7117414115