Alzheimer's disease (AD) affects more than 6 million American but no cures and few effective treatmentsare available. Genome-wide association studies (GWAS) have uncovered thousands of segregating mutationsthat significantly increase AD risk. Most of these variants alter non-protein-coding sequence and lack clearfunctional annotation, hindering efforts to translate risk-conferring mutations into curative or preventativetherapies. Heritability partitioning suggests that these variants likely perturb gene expression in glial cells(especially microglia), ultimately leading to AD pathology. Linking these variants - and their downstream effects- to specific regulatory networks and pathways has been hindered by a lack of cis-regulatory element maps forthese major glial cell classes and their subtypes. The proposed study addresses this critical knowledge gap byapplying a cutting-edge single cell multi-omic technology to postmortem human brain samples fromphenotypically normal donors and AD patients. Specifically, the chromatin accessibility or histone modificationswill be interrogated jointly with gene expression at single cell resolution in dorsolateral prefrontal cortex (DLPFC)from multiple donors, to identify and characterize the cell-type-specific gene regulatory elements that driveaberrant cell states and disease-relevant cellular responses in human AD brains. The single cell chromatin stateand gene expression atlases from phenotypically normal individuals will be compared to those from AD subjectsto determine the brain cell types, genes and regulatory elements that exhibit significant changes in pathologicalconditions. Finally, the newly generated cell-type resolved epigenome maps will be integrated with publicgenomic resources to provide functional annotation of the AD risk variants, identify disease-relevant cell types,prioritize genes, transcription factors, and molecular pathways for future mechanistic investigation. Results ofthe proposed study will provide a much-needed tool for study of AD pathogenesis and development of improvedAD therapies.
Public Health Relevance Statement: We proposed to use a novel high throughput technology platform to study the molecular and cellular makeup
of postmortem brain samples from Alzheimer's disease patients and controls at single cell resolution. The results
will improve our understanding of the cause and mechanisms of this neurodegenerative disease.
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