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
DOIs
StateAccepted/In press - 2021
Externally publishedYes

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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