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

被引：148

作者：

Mertens, Jerome ^{[1
,2
]}

Herdy, Joseph R. ^{[1
,2
,3
]}

Traxler, Larissa ^{[1
,2
]}

Schafer, Simon T. ^{[1
]}

Schlachetzki, Johannes C. M. ^{[4
]}

Bohnke, Lena ^{[1
,2
]}

Reid, Dylan A. ^{[1
]}

Lee, Hyungjun ^{[1
]}

Zangwill, Dina ^{[1
]}

Fernandes, Diana P. ^{[1
]}

Agarwal, Ravi K. ^{[1
]}

Lucciola, Raffaella ^{[1
]}

Zhou-Yang, Lucia ^{[2
]}

Karbacher, Lukas ^{[2
]}

Edenhofer, Frank ^{[5
,6
]}

Stern, Shani ^{[1
,7
]}

Horvath, Steve ^{[8
]}

Paquola, Apua C. M. ^{[1
,9
]}

Glass, Christopher K. ^{[4
]}

Yuan, Shauna H. ^{[3
,10
]}

Ku, Manching ^{[11
]}

Szucs, Attila ^{[12
]}

Goldstein, Lawrence S. B. ^{[3
,4
,13
]}

Galasko, Douglas ^{[3
]}

Gage, Fred H. ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Lab Genet, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Leopold Franzens Univ Innsbruck, Neural Aging Lab, Inst Mol Biol, CMBI, Tyrol, Austria

[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[5] Leopold Franzens Univ Innsbruck, Dept Genom Stem Cells & Regenerat Med, Inst Mol Biol, CMBI, Tyrol, Austria

[6] Leopold Franzens Univ Innsbruck, CMBI, Tyrol, Austria

[7] Univ Haifa, Fac Nat Sci, Sagol Dept Neurobiol, Haifa, Israel

[8] Univ Calif Los Angeles, Dept Human Genet, Dept Biostat, Los Angeles, CA USA

[9] Lieber Inst Brain Dev, Baltimore, MD USA

[10] Univ Minnesota Twin Cities, Dept Neurol, Minneapolis, MN USA

[11] Univ Freiburg, Fac Med, Dept Pediat & Adolescent Med, Div Pediat Hematol & Oncol,Med Ctr, Freiburg, Germany

[12] Eotvos Lorand Univ, Neuronal Cell Biol Res Grp, Budapest, Hungary

[13] Sanford Consortium Regenerat Med, La Jolla, CA USA

来源：

CELL STEM CELL | 2021年 / 28卷 / 09期

基金：

奥地利科学基金会; 欧盟地平线“2020”;

关键词：

REPROGRAMMED HUMAN NEURONS; GAMMA-SECRETASE ACTIVITY; CELL-CYCLE ACTIVATION; EPIGENETIC DRIFT; DNA-REPLICATION; OPEN CHROMATIN; DISEASE; GENE; SIGNATURES; GENERATION;

D O I：

10.1016/j.stem.2021.04.004

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：1533 / +

页数：22

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