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• W2912665828 abstract "Early-Onset Familial Alzheimer9s Disease (EOFAD) is a dominantly inherited neurodegenerative disorder elicited by mutations in the PSEN1, PSEN2, and APP genes. Hallmark pathological changes and symptoms observed, namely the accumulation of misfolded Amyloid-β (Aβ) in plaques and Tau aggregates in neurofibrillary tangles associated with memory loss and cognitive decline, are understood to be temporally accelerated manifestations of the more common sporadic Late-Onset Alzheimer9s Disease. The complete penetrance of EOFAD-causing mutations has allowed for experimental models which have proven integral to the overall understanding of AD. However, the failure of pathology-targeting therapeutic development suggests that the formation of plaques and tangles may be symptomatic and not describe the etiology of the disease. Here, we use an integrative, multi-omics approach and systems-level analysis in hiPSC-derived neurons to generate a mechanistic disease model for EOFAD. Using patient-specific cells from donors harboring mutations in PSEN1 differentiated into neurons, we characterize the disease-related gene expression and chromatin accessibility changes by RNA-Seq, ATAC-Seq, and histone methylation ChIP-Seq. Here, we show that the defining disease-causing mechanism of EOFAD is dedifferentiation, causing neurons to traverse the lineage-defining chromatin landscape along an alternative axis to a mixed-lineage cell state with gene signature profiles indicative of less-defined ectoderm as well as non-ectoderm lineages via REST-mediated repression of neuronal lineage specification gene programs and the activation of non-specific germ layer precursor gene programs concomitant with modifications in chromatin accessibility. Further, a reanalysis of existing transcriptomic data from PSEN1 patient brain samples demonstrates that the mechanisms identified in our experimental system recapitulate EOFAD in the human brain. Our results comprise a disease model which describes the mechanisms culminating in dedifferentiation that contribute to neurodegeneration." @default.
• W2912665828 created "2019-02-21" @default.
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• W2912665828 date "2019-11-18" @default.
• W2912665828 modified "2023-09-27" @default.
• W2912665828 title "Dedifferentiation and neuronal repression define Familial Alzheimer’s Disease" @default.
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