Dedifferentiation and neuronal repression define familial Alzheimer's disease

Andrew B. Caldwell, Qing Liu, Gary P. Schroth, Douglas R. Galasko, Shauna H. Yuan, Steven L. Wagner, Shankar Subramaniam

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer's disease uncovered here offer key insights for therapeutic interventions.

Original languageEnglish (US)
Article numbereaba5933
JournalScience Advances
Volume6
Issue number46
DOIs
StatePublished - Oct 2020
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by the Alzheimer's Association New Investigator Research Award (NIRG-14-322164) (to S.H.Y.); NIH grants P50 AGO5131 (to D.R.G.), U01 NS 074501-05 (to S.L.W.), R01 LM012595 (to S.S.), U01 CA198941 (to S.S.), U01 DK097430 (to S.S.), R01 HD084633 (to S.S.), and R01 HL106579-07 (to S.S.); NSF grant STC CCF-0939370 (to S.S.); Veterans Affairs RR&D 1I01RX002259 (to S.L.W.); and Cure Alzheimer's Fund (CAF) grants (to S.L.W.).

Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.

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