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

Cell Stem Cell. 2021 Sep 2;28(9):1533-1548.e6. doi: 10.1016/j.stem.2021.04.004. Epub 2021 Apr 27.

Authors

Jerome Mertens¹, Joseph R Herdy², Larissa Traxler³, Simon T Schafer⁴, Johannes C M Schlachetzki⁵, Lena Böhnke³, Dylan A Reid⁴, Hyungjun Lee⁴, Dina Zangwill⁴, Diana P Fernandes⁴, Ravi K Agarwal⁴, Raffaella Lucciola⁴, Lucia Zhou-Yang⁶, Lukas Karbacher⁶, Frank Edenhofer⁷, Shani Stern⁸, Steve Horvath⁹, Apua C M Paquola¹⁰, Christopher K Glass⁵, Shauna H Yuan¹¹, Manching Ku¹², Attila Szücs¹³, Lawrence S B Goldstein¹⁴, Douglas Galasko¹⁵, Fred H Gage¹⁶

Affiliations

¹ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria. Electronic address: jerome.mertens@uibk.ac.at.
² Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
³ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria.
⁴ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
⁵ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
⁶ Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria.
⁷ Department of Genomics, Stem Cells & Regenerative Medicine, Institute of Molecular Biology, CMBI, Institute of Molecular Biology and CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria.
⁸ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
⁹ Department of Human Genetics, Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Lieber Institute for Brain Development, Baltimore, MD, USA.
¹¹ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; University of Minnesota, Twin Cities, Department of Neurology, Minneapolis, MN, USA.
¹² Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
¹³ Neuronal Cell Biology Research Group, Eötvös Loránd University, Budapest, Hungary.
¹⁴ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
¹⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA. Electronic address: gage@salk.edu.

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.

Publication types

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

MeSH terms

Aged
Aging
Alzheimer Disease*
Fibroblasts
Humans
Induced Pluripotent Stem Cells*
Neurons

Abstract

Publication types

MeSH terms

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