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• W2980373310 abstract "Alzheimer's disease (AD) is genetically, pathogenically and clinically heterogenous and likely involves multiple pathways and cell types. Many genetic variants associated with the development of AD map to genomic regions associated with genes known to function in the formation and transfer of endosomes. The molecular mechanisms by which the risk alleles influence AD pathogenesis is not known. We hypothesize that a higher load of endosomal pathway variants results in altered biology of neurons and microglia. Single nuclei RNA-seq and ATAC-seq analyses can be employed to identify epigenomic and transcriptomic dysregulation associated with high endosomal pathway genetic risk. Establishing a method to incorporate inherited genetic risk with cellular phenotype may help identify biological networks involved in AD pathogenesis. We developed an endosome function specific polygenic risk score (ePRS) for established AD risk alleles. Rapid autopsy brain tissue (post-mortem interval <8hrs) was collected through the University of Washington ADRC and samples with an ePRS from the highest and lowest quartiles were taken for analysis. Neuronal and myeloid cell nuclei were isolated using fluorescence activated cells sorting. The nuclei preparations were used to generate single nuclei transcriptomes and chromatin landscape maps for each cell type. Leptomeningeal cells from the same brain samples will be either trans-differentiated into neurons or reprogrammed to induced pluripotent stem cells followed by differentiation into neurons or microglia for functional studies. The ePRS correlates with presence of AD and allows the stratification of cases investigated with epigenomic and transcriptomic analysis, iPSC reprogramming, and subsequent neural cell differentiation. Integration of epigenetic and transcriptomic can identify cell type specific patterns associated with the presence of high or low ePRS. Identifying cellular phenotypes associated with high ePRS in neuropathologically confirmed AD is an important step in the development of a platform to screen potential therapies aimed at tailored modulation of the pathogenic impact of high ePRS. Leptomeningeal cell derived neurons and microglia can be used to interrogate AD associated cellular phenotypes identified by cell type specific epigenomic and transcriptomic analysis. Assessing impact of genetic risk loci on these measures may help establish mechanisms by which genetic variants confer increased risk for AD." @default.
• W2980373310 created "2019-10-25" @default.
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• W2980373310 date "2019-07-01" @default.
• W2980373310 modified "2023-10-16" @default.
• W2980373310 title "P4-479: METHODS TO ASSESS CELL-TYPE-SPECIFIC, BIOLOGICAL NETWORKS OF ALZHEIMER'S DISEASE" @default.
• W2980373310 doi "https://doi.org/10.1016/j.jalz.2019.08.025" @default.
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