Cited by 599Alzheimer's disease research and treatmentsPluripotent Stem Cells ResearchDementia and Cognitive Impairment Research

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Modeling familial Alzheimer's disease with induced pluripotent stem cells

Yagi, Takuya, Ito, Daisuke, Okada, Yohei, Akamatsu, Wado, Nihei, Yoshihiro, Yoshizaki, Takahito, Yamanaka, Shinya, Okano, Hideyuki, Suzuki, Norihiro·2011·Human Molecular Genetics

DOI 10.1093/hmg/ddr394

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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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Self-citation

Authors: Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., & Suzuki, N.
Affiliations: Keio University (JP)
ORCID: Yagi, Takuya
Ito, Daisuke
Okada, Yohei
Akamatsu, Wado
Nihei, Yoshihiro
Yamanaka, Shinya
Okano, Hideyuki
Suzuki, Norihiro
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
DOI: 10.1093/hmg/ddr394
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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Modeling familial Alzheimer's disease with induced pluripotent stem cells

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