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 journalArticle

315 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 languageEnglish
Article numberddr394
Pages (from-to)4530-4539
Number of pages10
JournalHuman Molecular Genetics
Volume20
Issue number23
DOIs
Publication statusPublished - 2011 Dec

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Induced Pluripotent Stem Cells
Alzheimer Disease
Presenilin-2
Presenilin-1
Neurons
Amyloid
Neurodegenerative Diseases
Presenilins
Amyloid Precursor Protein Secretases
Mutation
Memory Disorders
Dementia
Cell Differentiation
Fibroblasts
Technology
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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.

In: Human Molecular Genetics, Vol. 20, No. 23, ddr394, 12.2011, p. 4530-4539.

Research output: Contribution to journalArticle

Yagi, T, Ito, D, Okada, Y, Akamatsu, W, Nihei, Y, Yoshizaki, T, Yamanaka, S, Okano, H & Suzuki, N 2011, 'Modeling familial Alzheimer's disease with induced pluripotent stem cells', Human Molecular Genetics, vol. 20, no. 23, ddr394, pp. 4530-4539. https://doi.org/10.1093/hmg/ddr394
Yagi, Takuya ; Ito, Daisuke ; Okada, Yohei ; Akamatsu, Wado ; Nihei, Yoshihiro ; Yoshizaki, Takahito ; Yamanaka, Shinya ; Okano, Hideyuki ; Suzuki, Norihiro. / Modeling familial Alzheimer's disease with induced pluripotent stem cells. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 23. pp. 4530-4539.
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