REST and neural gene network dysregulation in iPSC models of Alzheimer’s disease
Open accessAbstract
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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Three ApoE3 and ApoE4 isogenic iPSC pairs were used to determine the effect of APOE4 genotype without inter-donor variability.
“Three ApoE3 and ApoE4 isogenic iPSCs pairs were used to determine the effect of APOE4 genotype without inter-donor variability.5”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [40]
The Results section (‘APOE4 Induces Early Neuronal Differentiation and Dysregulation of REST’; page not provided) says the authors used isogenic iPSC lines differing only in APOE genotype to study its effects, which supports the rationale of avoiding inter-donor differences within a comparison. It describes editing lines from two donor backgrounds, not using three isogenic APOE3/APOE4 pairs. The three biological replicates reported in Methods are organoid samples, not three pairs. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGene expression alteration of Pcdh-γC5 has been detected in the brain of Alzheimer's disease patients and animal models of Alzheimer's disease, as well as neural cells generated from human iPSCs that express APOE4.
“The gene expression alteration of Pcdh-γC5 has also been detected in the brain of AD patients and animal models of AD, as well as neural cells generated from human iPSCs that express APOE4, a prevalent genetic AD risk factor (Nativio et al., 2018;Meyer et al., 2019).”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Meyer et al., 2019
The Results section on APOE4 and neuronal differentiation reports altered expression of other genes in APOE4 iPSC-derived neural progenitors and cerebral organoids. Our copy does not identify Pcdh-γC5 among them; searches for Pcdh-γC5, PCDHGC5, and protocadherin found no passage establishing the gene-specific claim. It also does not establish that alteration in AD patient or animal-model brains. (LLM, conf=0.80)
Experimental — accuracy not yet measuredFor studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and complement isogenic iPSC strategies.
“Collectively, for studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and thus complement isogenic iPSC strategies (van der Kant et al., 2019; Meyer et al., 2019; Woodruff et al., 2013).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Meyer et al., 2019
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- Authors
- Meyer, K., Feldman, H. M., Lu, T., Drake, D., Lim, E. T., Ling, K.-H., Bishop, N. A., Pan, Y., Seo, J., Lin, Y.-T., Su, S. C., Church, G. M., Tsai, L.-H., & Yankner, B. A.
- Affiliations
- Harvard University (US)
- Universiti Putra Malaysia (MY)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Yankner, Bruce A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 26
- Issue
- 5
- Pages
- 1112-1127.e9
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6386196
- OpenAlex
- W2913604250
- Cited by
- 216
- References
- 52
- Citations by year
- 2026: 12 · 2025: 26 · 2024: 31 · 2023: 25 · 2022: 31 · 2021: 43 · 2020: 38 · 2019: 10
- FWCI
- 21.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Universiti Putra Malaysia Institutional Repository (Universiti Putra Malaysia) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (DP1OD006849, R01AG046174, RF1AG048056, RF1AG048029, RM1HG008525)
- Paul F. Glenn Foundation for Medical Research
- Fidelity Biosciences Research Initiative
- Robert A. and Renee E. Belfer Family Foundation
- Cure Alzheimer's Fund
- DFG (ME 4810/1-1)
- IBRO/ISN
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Alzheimer's disease, rest, APOE ε4, induced pluripotent stem cells, iPSC-derived neural progenitor cells, iPSC-derived neurons, brain organoids, neuronal differentiation, neurogenesis, synaptic transmission, gene regulatory networks, nuclear lamina, sporadic Alzheimer's disease
- MeSH terms
- RE1-Silencing Transcription Factor, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Cell Differentiation, Fibroblasts, Gene Expression Regulation, Humans, Middle Aged, Neurons, Repressor Proteins, Amyloid beta-Peptides, Nuclear Lamina, Gene Regulatory Networks, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells, Cellular Reprogramming
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