Diana Acosta (United States of America)
The Ohio State University Wexner Medical Center NeuroscienceAuthor Of 1 Presentation
MULTI-OMICS APPROACH TO EXPLORE MECHANISMS UNDERLYING THE SELECTIVE VULNERABILITY IN AD
Abstract
Aims
A major challenge for the development of effective, disease-modifying therapies for Alzheimer’s disease (AD) has been our incomplete understanding of the selective cellular and regional vulnerability in AD, which is a devastating neurodegenerative condition. Therefore, there is an urgent need to uncover the molecular mechanisms underlying this selective vulnerability.
Methods
We used 10x Genomics single nucleus Multiome ATAC + Gene Expression and Visium Spatial Transcriptomics to provide the transcriptomic and epigenomic signatures and spatial transcriptomic maps for the human middle temporal gyrus (MTG), a brain region affected early in AD. RNAscope HiPlex assay was used to validate identified genes at the single cell level.
Results
We identified differentially expressed genes (DEGs), enriched pathways, and regulons (i.e., transcription factors) in each cell type between AD and controls. We also identified layer specific DEGs associated with the architecture of human MTG and DEGs associated with Aβ and/or tau pathology. Furthermore, we used weighted gene co-expression network analysis to determine hub genes controlling cell-type-specific and region-specific responses to Aβ and tau pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications between neurons and glia, which may contribute to the cellular and regional vulnerability in AD. In addition, 14 representative DEGs (e.g. CD9, SPP1, CRYAB, etc.) in four main brain cell types were validated by RNAscope HiPlex assay.
Conclusions
Together, our results provide a list of genes and pathways associated with the selective vulnerability in AD. Future research will validate the contributions of these representative DEGs to selective vulnerability in AD using in vitro and in vivo models. The experimental strategy we propose in this study can be applied to many other neurodegenerative diseases.