Modeling familial Alzheimer's disease with induced pluripotent stem cells

Takuya Yagi; Daisuke Ito; Yohei Okada; Wado Akamatsu; Yoshihiro Nihei; Takahito Yoshizaki; Shinya Yamanaka; Hideyuki Okano; Norihiro Suzuki

doi:10.1093/hmg/ddr394

Modeling familial Alzheimer's disease with induced pluripotent stem cells

Takuya Yagi, Daisuke Ito, Yohei Okada, Wado Akamatsu, Yoshihiro Nihei, Takahito Yoshizaki, Shinya Yamanaka, Hideyuki Okano, Norihiro Suzuki

Research output: Contribution to journal › Article › peer-review

465 Citations (Scopus)

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 g-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.

Original language	English
Article number	ddr394
Pages (from-to)	4530-4539
Number of pages	10
Journal	Human molecular genetics
Volume	20
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddr394
Publication status	Published - 2011 Dec

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddr394

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@article{642972827c1f4f73966e7254473c7c55,

title = "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 g-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.",

author = "Takuya Yagi and Daisuke Ito and Yohei Okada and Wado Akamatsu and Yoshihiro Nihei and Takahito Yoshizaki and Shinya Yamanaka and Hideyuki Okano and Norihiro Suzuki",

note = "Funding Information: T.Y. is a research fellow of the Japan Society for the Promotion of Science. This work was supported by grants from Eisai Co. Ltd (to D.I. and N.S.) and the project for realization of regenerative medicine from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H.O. We thank Mari Fujiwara (Core Instrumentation Facility, Keio University School of Medicine) for the microarray analysis and Satoko Iwasawa (Department of Preventive Medicine and Public Health, School of Medicine, Keio University) for helpful advice about statistical analysis. We also thank Dr Xu Huaxi for providing the T44 Tau pSG5 plasmid (Sanford-Burnham Medical Research Institute). Funding Information: This work was supported by grants from Eisai Co. Ltd (to D.I. and N.S.), the Research Fellowship grant of the Japan Society for the Promotion of Science (to T.Y.), and the Project for Realization of Regenerative Medicine, and Support for Core Institutes for iPS Cell Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.O.).",

year = "2011",

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doi = "10.1093/hmg/ddr394",

language = "English",

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T1 - Modeling familial Alzheimer's disease with induced pluripotent stem cells

AU - Yagi, Takuya

AU - Ito, Daisuke

AU - Okada, Yohei

AU - Akamatsu, Wado

AU - Nihei, Yoshihiro

AU - Yoshizaki, Takahito

AU - Yamanaka, Shinya

AU - Okano, Hideyuki

AU - Suzuki, Norihiro

N1 - Funding Information: T.Y. is a research fellow of the Japan Society for the Promotion of Science. This work was supported by grants from Eisai Co. Ltd (to D.I. and N.S.) and the project for realization of regenerative medicine from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H.O. We thank Mari Fujiwara (Core Instrumentation Facility, Keio University School of Medicine) for the microarray analysis and Satoko Iwasawa (Department of Preventive Medicine and Public Health, School of Medicine, Keio University) for helpful advice about statistical analysis. We also thank Dr Xu Huaxi for providing the T44 Tau pSG5 plasmid (Sanford-Burnham Medical Research Institute). Funding Information: This work was supported by grants from Eisai Co. Ltd (to D.I. and N.S.), the Research Fellowship grant of the Japan Society for the Promotion of Science (to T.Y.), and the Project for Realization of Regenerative Medicine, and Support for Core Institutes for iPS Cell Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.O.).

PY - 2011/12

Y1 - 2011/12

N2 - 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 g-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.

AB - 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 g-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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SN - 0964-6906

VL - 20

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JO - Human molecular genetics

JF - Human molecular genetics

IS - 23

M1 - ddr394

ER -

Modeling familial Alzheimer's disease with induced pluripotent stem cells

Abstract

ASJC Scopus subject areas

UN SDGs

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