Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients

Jerome Mertens, Joseph R. Herdy, Larissa Traxler, Simon T. Schafer, Johannes C.M. Schlachetzki, Lena Böhnke, Dylan A. Reid, Hyungjun Lee, Dina Zangwill, Diana P. Fernandes, Ravi K. Agarwal, Raffaella Lucciola, Lucia Zhou-Yang, Lukas Karbacher, Frank Edenhofer, Shani Stern, Steve Horvath, Apua C.M. Paquola, Christopher K. Glass, Shauna H. YuanManching Ku, Attila Szücs, Lawrence S.B. Goldstein, Douglas Galasko, Fred H. Gage

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalCell Stem Cell
Volume28
Issue number9
Early online dateApr 21 2021
DOIs
StatePublished - Sep 2 2021

Bibliographical note

Funding Information:
We are grateful to all donors participating in this study. We thank F. Schön, D. Frantal, K. Diffenderfer, L. Moore, C. Herrera, and M. Suarez-Cubero for technical assistance; J. Ouyang for sharing data; M.L. Gage and A.A. Mansour for editorial comments; and https://www.mertensdesignlab.com for illustrations. This work was supported by the European Union (EU) grants ERC-STG-2019-852086 and H2020-MSCA-IF-2017-797205 ; the BrightFocus Foundation ; National Institute on Aging (NIA) grant K99-AG056679 ; the Chen Foundation ; Austrian Science Fund grant FWF-I5057 (J.M.); American Heart Association (AHA)-Allen Initiative award 19PABH134610000 ; the Paul G. Allen Family Foundation ; NIA R01 grants AG056306 , AG056511 , and AG057706 ; the JPB Foundation ; the Leona M. and Harry B. Helmsley Charitable Trust ; Annette C. Merle-Smith ; the G. Harold & Leila Y. Mathers Charitable Foundation ; the Ray and Dagmar Dolby Family Fund ; Stichting ASC Academy ; California Institute for Regenerative Medicine (CIRM) grant RT2-01927 (F.H.G.); the Austrian Science Fund FWF-SPIN (L.T.); the Alzheimer's Association Research Fellowship (D.A.R.); the Alzheimer Nederland Foundation (D.P.F.); Deutsche Forschungsgemeinschaft grant DFG-SFB1160-IMPATH ; the German Academic Exchange Service (DAAD) (M.K.); the Zuckerman STEM Leadership Program (S.S.); the Austrian Marshall Plan Foundation (L.T., L.K.); the Dr. Otto Seibert-Foundation (L.K.); the EU Joint Programme – Neurodegenerative Disease Research (JPND) MADGIC program through the Austrian Bundesministerium für Bildung, Wissenschaft und Forschung, Bildungsministerium (BMBWF) (F.E.); the Hungarian ANN-135291 (A.S.); and the Shiley-Marcos Alzheimer’s Disease Research Center (ADRC; AG062429 ) at the University of California, San Diego (UCSD).

Funding Information:
We are grateful to all donors participating in this study. We thank F. Sch?n, D. Frantal, K. Diffenderfer, L. Moore, C. Herrera, and M. Suarez-Cubero for technical assistance; J. Ouyang for sharing data; M.L. Gage and A.A. Mansour for editorial comments; and https://www.mertensdesignlab.com for illustrations. This work was supported by the European Union (EU) grants ERC-STG-2019-852086 and H2020-MSCA-IF-2017-797205; the BrightFocus Foundation; National Institute on Aging (NIA) grant K99-AG056679; the Chen Foundation; Austrian Science Fund grant FWF-I5057 (J.M.); American Heart Association (AHA)-Allen Initiative award 19PABH134610000; the Paul G. Allen Family Foundation; NIA R01 grants AG056306, AG056511, and AG057706; the JPB Foundation; the Leona M. and Harry B. Helmsley Charitable Trust; Annette C. Merle-Smith; the G. Harold & Leila Y. Mathers Charitable Foundation; the Ray and Dagmar Dolby Family Fund; Stichting ASC Academy; California Institute for Regenerative Medicine (CIRM) grant RT2-01927 (F.H.G.); the Austrian Science Fund FWF-SPIN (L.T.); the Alzheimer's Association Research Fellowship (D.A.R.); the Alzheimer Nederland Foundation (D.P.F.); Deutsche Forschungsgemeinschaft grant DFG-SFB1160-IMPATH; the German Academic Exchange Service (DAAD) (M.K.); the Zuckerman STEM Leadership Program (S.S.); the Austrian Marshall Plan Foundation (L.T. L.K.); the Dr. Otto Seibert-Foundation (L.K.); the EU Joint Programme ? Neurodegenerative Disease Research (JPND) MADGIC program through the Austrian Bundesministerium f?r Bildung, Wissenschaft und Forschung, Bildungsministerium (BMBWF) (F.E.); the Hungarian ANN-135291 (A.S.); and the Shiley-Marcos Alzheimer's Disease Research Center (ADRC; AG062429) at the University of California, San Diego (UCSD). Conceptualization, J.M. D.G. and F.H.G.; Methodology, J.M. J.R.H. L.T. S.T.S. J.C.M.S. and L.B.; Software, J.M. J.R.H. S.T.S. J.C.M.S. L.K. S.H. A.C.M.P. and M.K.; Formal Analysis, J.M. J.R.H. L.T. S.T.S. J.C.M.S. L.B. D.P.F. R.L. L.Z.-Y. L.K. S.S. A.C.M.P. S.H.Y. and M.K.; Investigation, J.M. J.R.H. L.T. S.T.S. J.C.M.S. L.B. D.A.R. H.L. D.Z. D.P.F. R.K.A. R.L. L.Z.-Y. L.K. S.H.Y. M.K. and A.S.; Resources, J.M. F.E. C.K.G. M.K. L.S.B.G. D.G. and F.H.G.; Data Curation, J.M. J.R.H. L.K. and A.C.M.P.; Writing ? Original Draft, J.M. and F.H.G.; Writing ? Review & Editing, J.M. D.G. and F.H.G. F.H.G. is an advisory board member of Cell Stem Cell.

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • Alzheimer's disease
  • aging
  • de-differentiation
  • induced neurons (iNs)
  • neuronal cell cycle re-entry
  • rejuvenation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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