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

• Published in: Cell reports (Cambridge) Vol. 26; no. 5; pp. 1112 - 1127.e9
• Main Authors: 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, Su, Susan C., Church, George M., Tsai, Li-Huei, Yankner, Bruce A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2019; Elsevier
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; apolipoprotein E; Apolipoproteins E - metabolism; Cell Differentiation - genetics; Cellular Reprogramming - genetics; epigenetic; Fibroblasts - pathology; Gene Expression Regulation; Gene Regulatory Networks; Humans; induced pluripotent stem cell; Induced Pluripotent Stem Cells - metabolism; Middle Aged; neural differentiation; neural progenitor; Neural Stem Cells - metabolism; neurogenesis; Neurogenesis - genetics; Neurons - metabolism; Nuclear Lamina - metabolism; organoid; polycomb; Repressor Proteins - metabolism; REST; REST; induced pluripotent stem cell; Alzheimer’s disease; epigenetic; polycomb; apolipoprotein E; neurogenesis; neural progenitor; neural differentiation; organoid
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.01.023

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. [Display omitted] •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.