REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease
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 (N...
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Published in | Cell reports (Cambridge) Vol. 26; no. 5; pp. 1112 - 1127.e9 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
29.01.2019
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•Sporadic AD and apolipoprotein E4 (APOE4) share a common neural transcriptome•AD and APOE4 neural progenitors exhibit altered neural differentiation•Loss of function of REST alters transcription and differentiation in AD and APOE4•Nuclear lamina disruption associated with AD and APOE4 may impair REST function
Meyer et al. derive neural progenitors, neurons, and cerebral organoids from sporadic Alzheimer’s disease (SAD) and APOE4 gene-edited iPSCs. SAD and APOE4 expression alter the neural transcriptome and differentiation in part through loss of function of the transcriptional repressor REST. Thus, neural gene network dysregulation may lead to Alzheimer’s disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS K.M., H.M.F., T.L., K.-H.L., and Y.P. performed experiments. E.T.L. and G.M.C. generated cerebral organoids. D.D. performed bioinformatics analysis. S.C.S., J.S., and L.-H.T. analyzed electrophysiology. Y.-T.L. generated APOE isogenic lines. N.A.B. generated iPSC lines. K.M., H.M.F., and B.A.Y. wrote the manuscript. B.A.Y. supervised the study. |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2019.01.023 |