Microglial Changes in Alzheimer's Progression
Summary
In their study, they assessed the transcriptomes of over 150,000 microglia from 443 individuals, pinpointing 12 distinct transcriptional states linked to Alzheimer's disease (AD). Despite challenges in mapping disease-associated microglial (DAM) states in mouse models to human experiences, they leveraged gene signatures combined with snATAC-seq to discover essential regulatory networks for these states. By using stem-cell-derived microglia-like cells, they evaluated transcription factors' capacity to guide microglial states. They identified state-specific shifts linked to AD progression stages, connected AD-risk genes with particular microglial states, and highlighted potential regulatory pathways in AD's evolution, offering a deeper understanding of microglia's role in AD.
Fig.1 Graphical abstract1.
Research Criteria
The article focuses on understanding the altered microglial states that affect neuroinflammation, neurodegeneration, and disease. The study reports on 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects with diverse Alzheimer's disease (AD) pathological phenotypes. They identified 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. They also identified 1,542 AD-differentially-expressed genes and integrated epigenomic, transcriptomic, and motif information to infer upstream regulators of microglial cell states.
Sample Type
The study utilized single-nucleus transcriptomes and epigenomes of human microglia. The samples were derived from 443 human subjects spanning various brain regions and diverse clinical and pathological states related to Alzheimer's disease.
Result—Microglia Transcriptional States are Being Studied
In an intricate exploration of microglial transcriptional states within the aging human brain, researchers meticulously analyzed the transcriptomes of over 150,000 single microglia nuclei, sourced from both Alzheimer's Disease (AD) patients and control subjects. This comprehensive study, encompassing six distinct brain regions, revealed 12 unique microglial states, each discerned by their molecular signatures and functions. Notably, the homeostatic microglia exhibited markers like P2RY12, while the lipid-processing state was characterized by lipid homeostasis and cholesterol efflux enrichment. Intriguingly, certain states, such as the lipid-processing MG4 and inflammatory MG8, were found to be significantly more prevalent in AD brains. Concurrently, in situ hybridization experiments validated the prominence of lipid-processing and inflammatory states in AD-afflicted brains. Furthermore, the study discerned that Disease-Associated Microglia (DAM) signatures in the human AD brain spanned multiple states, underscoring the complexity and heterogeneity of microglial responses in neurodegenerative conditions.
Fig.2 In elderly human brains, microglial transcriptional states1.
Result—Prediction of Microglial Upstream Transcription Factors
Delving deeply into the nuances of microglial states using single-nucleus ATAC-seq (snATAC-seq) on human postmortem brain tissues, researchers discerned three distinct epigenomic states: a homeostatic state (HOM) and two activated states (ACT1 and ACT2). P2RY12, a homeostatic marker, exhibited diminished accessibility in activated states, while CCL3 and SPP1 indicated potential roles in immune response and cell activation respectively. Interestingly, microglial transcriptional heterogeneity surpassed that of chromatin accessibility. A subsequent analysis of accessible peaks revealed associations with genes involved in calcineurin-NFAT signaling, lipoprotein particle clearance, and blood-brain barrier (BBB) functions. Probing the regulatory mechanisms, transcription factors (TFs) such as SPI1, IRF8, and STAT1 were ubiquitously enriched across states, while others like ARID5B and ID2 were specific to activated states. Co-accessibility patterns further elucidated potential TFs modulating microglial states, with FOXO3 and HIF1A playing pivotal roles in inflammatory responses and glycolytic metabolism. The intricate web of TF-target interactions suggests a cooperative transcriptional regulation, ensuring system robustness and specialized gene expression.
Fig.3 Microglial states are regulated by TFs1.
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Reference
- Sun, Na, et al. "Human microglial state dynamics in Alzheimer's disease progression." Cell 186.20 (2023): 4386-4403.
