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Cell Rep. 2019 Jan 29;26(5):1112-1127.e9. doi: 10.1016/j.celrep.2019.01.023.

REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease.

Author information

1
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
3
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
4
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bruce_yankner@hms.harvard.edu.

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.

KEYWORDS:

Alzheimer’s disease; REST; apolipoprotein E; epigenetic; induced pluripotent stem cell; neural differentiation; neural progenitor; neurogenesis; organoid; polycomb

PMID:
30699343
DOI:
10.1016/j.celrep.2019.01.023
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