Dedifferentiation and neuronal repression define familial Alzheimer's disease.

ABSTRACT: Identifying the systems-level mechanisms that lead to Alzheimer's disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)-derived neurons from donor patients with early-onset familial Alzheimer's disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transc

SUBMITTER: Caldwell AB 

PROVIDER: S-EPMC7673760 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature