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. Yuan; Manching Ku; Attila Szücs; Lawrence S.B. Goldstein; Douglas Galasko; Fred H. Gage

doi:10.1016/j.stem.2021.04.004

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

Department of Neurobiology

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	1533-1548.e6
Journal	Cell Stem Cell
Volume	28
Issue number	9
DOIs	https://doi.org/10.1016/j.stem.2021.04.004
State	Published - 2 Sep 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

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2021.04.004

Cite this

Mertens, J., Herdy, J. R., Traxler, L., Schafer, S. T., Schlachetzki, J. C. M., Böhnke, L., Reid, D. A., Lee, H., Zangwill, D., Fernandes, D. P., Agarwal, R. K., Lucciola, R., Zhou-Yang, L., Karbacher, L., Edenhofer, F., Stern, S., Horvath, S., Paquola, A. C. M., Glass, C. K., ... Gage, F. H. (2021). Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients. Cell Stem Cell, 28(9), 1533-1548.e6. https://doi.org/10.1016/j.stem.2021.04.004

@article{9b72cb3c9ded4d19ab1be2d5c79f6555,

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?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: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = sep,

day = "2",

doi = "10.1016/j.stem.2021.04.004",

language = "English",

volume = "28",

pages = "1533--1548.e6",

journal = "Cell Stem Cell",

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Mertens, J, Herdy, JR, Traxler, L, Schafer, ST, Schlachetzki, JCM, Böhnke, L, Reid, DA, Lee, H, Zangwill, D, Fernandes, DP, Agarwal, RK, Lucciola, R, Zhou-Yang, L, Karbacher, L, Edenhofer, F, Stern, S, Horvath, S, Paquola, ACM, Glass, CK, Yuan, SH, Ku, M, Szücs, A, Goldstein, LSB, Galasko, D & Gage, FH 2021, 'Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients', Cell Stem Cell, vol. 28, no. 9, pp. 1533-1548.e6. https://doi.org/10.1016/j.stem.2021.04.004

TY - JOUR

T1 - Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients

AU - Mertens, Jerome

AU - Herdy, Joseph R.

AU - Traxler, Larissa

AU - Schafer, Simon T.

AU - Schlachetzki, Johannes C.M.

AU - Böhnke, Lena

AU - Reid, Dylan A.

AU - Lee, Hyungjun

AU - Zangwill, Dina

AU - Fernandes, Diana P.

AU - Agarwal, Ravi K.

AU - Lucciola, Raffaella

AU - Zhou-Yang, Lucia

AU - Karbacher, Lukas

AU - Edenhofer, Frank

AU - Stern, Shani

AU - Horvath, Steve

AU - Paquola, Apua C.M.

AU - Glass, Christopher K.

AU - Yuan, Shauna H.

AU - Ku, Manching

AU - Szücs, Attila

AU - Goldstein, Lawrence S.B.

AU - Galasko, Douglas

AU - Gage, Fred H.

N1 - 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)

PY - 2021/9/2

Y1 - 2021/9/2

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - aging

KW - de-differentiation

KW - induced neurons (iNs)

KW - neuronal cell cycle re-entry

KW - rejuvenation

UR - http://www.scopus.com/inward/record.url?scp=85107039361&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2021.04.004

DO - 10.1016/j.stem.2021.04.004

M3 - Article

C2 - 33910058

AN - SCOPUS:85107039361

SN - 1934-5909

VL - 28

SP - 1533-1548.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 9

ER -

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

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