期刊
CELL STEM CELL
卷 28, 期 9, 页码 1533-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2021.04.004
关键词
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资金
- European Union (EU) [ERC-STG2019-852086, H2020-MSCA-IF-2017-797205]
- BrightFocus Foundation
- National Institute on Aging (NIA) [K99-AG056679]
- Chen Foundation
- Austrian Science Fund [FWF-I5057]
- American Heart Association (AHA)-Allen Initiative [19PABH134610000]
- Paul G. Allen Family Foundation
- NIA R01 [AG056306, AG056511, AG057706]
- JPB Foundation
- e Leona M. and Harry B. Helmsley Charitable Trust
- G. Harold & Leila Y. Mathers Charitable Foundation
- Ray and Dagmar Dolby Family Fund
- Stichting ASC Academy
- California Institute for Regenerative Medicine (CIRM) [RT2-01927]
- Austrian Science Fund FWF-SPIN
- Alzheimer's Association Research Fellowship
- Alzheimer Nederland Foundation
- Deutsche Forschungsgemeinschaft [DFG-SFB1160-IMPATH]
- German Academic Exchange Service (DAAD)
- Zuckerman STEM Leadership Program
- Austrian Marshall Plan Foundation
- Dr. Otto Seibert-Foundation
- EU Joint Programme-Neurodegenerative Disease Research (JPND) MADGIC program through the Austrian Bundesministerium fur Bildung, Wissenschaft und Forschung, Bildungsministerium (BMBWF) [ANN-135291]
- Shiley-Marcos Alzheimer's Disease Research Center (ADRC) at the University of California, San Diego (UCSD) [AG062429]
Our study identifies AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.
Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.
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