REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease
Name
1-s2.0-S2211124719300324-main.pdf
Description
Published version
Size
6.22 MB
Format
Adobe PDF
Checksum (MD5)
b198da44fc39320013e66d6d8951b390
Author(s)
Meyer, Katharina
Feldman, Heather M.
Lu, Tao
Drake, Derek
Lim, Elaine T.
Ling, King-Hwa
Bishop, Nicholas A.
Pan, Ying
Seo, Jinsoo
Lin, Yuan-Ta
Date Issued
January 2019
Journal
Cell Reports
Publisher
Elsevier BV
Citation
Meyer, Katharina et al. "REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease." Cell Reports 26, 5 (January 2019): P1112-1127.e9 © 2019 The Author(s)
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.celrep.2019.01.023
