@article{3af913317f1c4995bc14c414b85358fa,
title = "Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients",
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.",
keywords = "Alzheimer's disease, aging, de-differentiation, induced neurons (iNs), neuronal cell cycle re-entry, rejuvenation",
author = "Jerome Mertens and Herdy, {Joseph R.} and Larissa Traxler and Schafer, {Simon T.} and Schlachetzki, {Johannes C.M.} and Lena B{\"o}hnke and Reid, {Dylan A.} and Hyungjun Lee and Dina Zangwill and Fernandes, {Diana P.} and Agarwal, {Ravi K.} and Raffaella Lucciola and Lucia Zhou-Yang and Lukas Karbacher and Frank Edenhofer and Shani Stern and Steve Horvath and Paquola, {Apua C.M.} and Glass, {Christopher K.} and Yuan, {Shauna H.} and Manching Ku and Attila Sz{\"u}cs and Goldstein, {Lawrence S.B.} and Douglas Galasko and Gage, {Fred H.}",
note = "Funding Information: We are grateful to all donors participating in this study. We thank F. Sch{\"o}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{\"u}r Bildung, Wissenschaft und Forschung, Bildungsministerium (BMBWF) (F.E.); the Hungarian ANN-135291 (A.S.); and the Shiley-Marcos Alzheimer{\textquoteright}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{\"o}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{\"u}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: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "2",
doi = "10.1016/j.stem.2021.04.004",
language = "English (US)",
volume = "28",
pages = "1533--1548.e6",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "9",
}