Age-dependent Instability of Mature Neuronal Fate in Induced Neurons from Alzheimer's Patients

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Apr 28

PMID 33910058

Citations 97

Authors

Jerome Mertens

Joseph R Herdy

Larissa Traxler

Simon T Schafer

Johannes C M Schlachetzki

Lena Bohnke

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 Szucs

Lawrence S B Goldstein

Douglas Galasko

Fred H Gage

Affiliations

Soon will be listed here.

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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