Fernandes, B. S. | Search bioRxiv

bioRxiv2024

Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease

Sporadic early-onset Alzheimers disease (sEOAD) represents a significant but less-studied subtype of Alzheimers disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.

neuroscience↗

bioRxiv2022

A single-cell atlas of the human brain in Alzheimer's disease and its implications for personalized drug repositioning

Alzheimers disease (AD) is a neurodegenerative disease with complex pathophysiology, and AD-dysregulated pathways are inconsistent across different brain regions and patients. Although single-cell RNA sequencing (scRNA-seq) has been performed in different regions of postmortem AD brains, the common and distinct molecular features among different regions remains largely unclear. This hinders the discovery of repurposable and personalized drugs for AD. We combined four scRNA-seq datasets and systematically investigated the common and distinct cellular responses, cell subpopulations, and transcription factors involved in AD. Moreover, we explored the transcriptional heterogeneity of different AD subtypes at the single-cell level. Finally, we conducted individual-based drug repurposing analysis to explore repurposable and personalized drugs. Six major brain cell types were detected after scRNA-seq batch-effect removal and noise cells filtering. Integration with genome-wide association studies (GWAS) summary statistics demonstrated that AD-susceptible genes were mainly enriched with differentially expressed genes (DEGs) in glial cells rather than neuronal cells. While most of DEGs were regulated in opposite directions among different cell types, cell-cell communication analysis revealed several common cellular interaction events involved in neurogenesis, as well as increased cell-cell adhesion. Our comprehensive drug repositioning analysis identified new candidates for AD treatment, including trichostatin, which was predicted to be broadly applicable to different identified AD subtypes, and vorinostat, which was specific for one subtype of AD. In summary, we delineated a cell-specific atlas of the AD transcriptome. Our work illustrated strong cellular heterogeneity in AD for defining AD subtypes. The cell-specific features are important for understanding AD etiology, progression, and drug discovery.

bioinformatics↗