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Modeling familial Alzheimer's disease with induced pluripotent stem cells
Abstract
Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbance. Mutations of presenilin 1 (PS1) and presenilin 2 (PS2) are causative factors for autosomal-dominant early-onset familial AD (FAD). Induced pluripotent stem cell (iPSC) technology can be used to model human disorders and provide novel opportunities to study cellular mechanisms and establish therapeutic strategies against various diseases, including neurodegenerative diseases. Here we generate iPSCs from fibroblasts of FAD patients with mutations in PS1 (A246E) and PS2 (N141I), and characterize the differentiation of these cells into neurons. We find that FAD-iPSC-derived differentiated neurons have increased amyloid β42 secretion, recapitulating the molecular pathogenesis of mutant presenilins. Furthermore, secretion of amyloid β42 from these neurons sharply responds to γ-secretase inhibitors and modulators, indicating the potential for identification and validation of candidate drugs. Our findings demonstrate that the FAD-iPSC-derived neuron is a valid model of AD and provides an innovative strategy for the study of age-related neurodegenerative diseases.
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“Multiple groups have characterized iPSC lines from donor cells from FAD and sAD patients, which show increased production of Aβ, particularly Aβ42, and tau hyperphosphorylation in comparison to iPSCs derived from age-matched non-demented controls [66, 82, 101, 175].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [175]
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Self-citation
Metadata
- Authors
- Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., & Suzuki, N.
- Affiliations
- Keio University (JP)
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-07
- Volume
- 20
- Issue
- 23
- Pages
- 4530-4539
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2157073241
- Cited by
- 599
- References
- 45
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 26 · 2023: 20 · 2022: 38 · 2021: 43 · 2020: 49 · 2019: 45 · 2018: 47 · 2017: 42 · 2016: 62 · 2015: 50 · 2014: 57 · 2013: 52 · 2012: 36
- FWCI
- 32.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23591254, 23650194, 23689017, 19002014)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- familial Alzheimer's disease, induced pluripotent stem cells, presenilin 1, presenilin 2, iPSC-derived neurons, gamma-secretase inhibitors, γ-secretase modulators, disease modeling, drug screening, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Cell Differentiation, Fibroblasts, Humans, Models, Biological, Mutation, Neurons, Protease Inhibitors, Teratoma, Amyloid beta-Peptides, Mice, SCID, Mice, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases, Induced Pluripotent Stem Cells
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