REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease.
Aged
Aged, 80 and over
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ metabolism
Apolipoproteins E
/ metabolism
Cell Differentiation
/ genetics
Cellular Reprogramming
/ genetics
Fibroblasts
/ pathology
Gene Expression Regulation
Gene Regulatory Networks
Humans
Induced Pluripotent Stem Cells
/ metabolism
Middle Aged
Neural Stem Cells
/ metabolism
Neurogenesis
/ genetics
Neurons
/ metabolism
Nuclear Lamina
/ metabolism
Repressor Proteins
/ metabolism
Alzheimer’s disease
REST
apolipoprotein E
epigenetic
induced pluripotent stem cell
neural differentiation
neural progenitor
neurogenesis
organoid
polycomb
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 01 2019
29 01 2019
Historique:
received:
03
08
2018
revised:
04
12
2018
accepted:
07
01
2019
entrez:
31
1
2019
pubmed:
31
1
2019
medline:
14
3
2020
Statut:
ppublish
Résumé
The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.
Identifiants
pubmed: 30699343
pii: S2211-1247(19)30032-4
doi: 10.1016/j.celrep.2019.01.023
pmc: PMC6386196
mid: NIHMS1519914
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Apolipoproteins E
0
RE1-silencing transcription factor
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1112-1127.e9Subventions
Organisme : NIMH NIH HHS
ID : R01 MH113279
Pays : United States
Organisme : NHGRI NIH HHS
ID : RM1 HG008525
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG048029
Pays : United States
Organisme : NIH HHS
ID : DP1 OD006849
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG048056
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046174
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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