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

Neurology

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99 Scopus citations

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 (US)
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 - Sep 2 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Keywords

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

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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

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

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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.",

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AU - Szücs, Attila

AU - Goldstein, Lawrence S.B.

AU - Galasko, Douglas

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

Abstract

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Keywords

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