Cargando…
Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secreta...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184175/ https://www.ncbi.nlm.nih.gov/pubmed/21984949 http://dx.doi.org/10.1371/journal.pone.0025788 |
_version_ | 1782213075333545984 |
---|---|
author | Yahata, Naoki Asai, Masashi Kitaoka, Shiho Takahashi, Kazutoshi Asaka, Isao Hioki, Hiroyuki Kaneko, Takeshi Maruyama, Kei Saido, Takaomi C. Nakahata, Tatsutoshi Asada, Takashi Yamanaka, Shinya Iwata, Nobuhisa Inoue, Haruhisa |
author_facet | Yahata, Naoki Asai, Masashi Kitaoka, Shiho Takahashi, Kazutoshi Asaka, Isao Hioki, Hiroyuki Kaneko, Takeshi Maruyama, Kei Saido, Takaomi C. Nakahata, Tatsutoshi Asada, Takashi Yamanaka, Shinya Iwata, Nobuhisa Inoue, Haruhisa |
author_sort | Yahata, Naoki |
collection | PubMed |
description | BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. METHODOLOGY/PRINCIPAL FINDINGS: We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. CONCLUSIONS/SIGNIFICANCE: These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation. |
format | Online Article Text |
id | pubmed-3184175 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31841752011-10-07 Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease Yahata, Naoki Asai, Masashi Kitaoka, Shiho Takahashi, Kazutoshi Asaka, Isao Hioki, Hiroyuki Kaneko, Takeshi Maruyama, Kei Saido, Takaomi C. Nakahata, Tatsutoshi Asada, Takashi Yamanaka, Shinya Iwata, Nobuhisa Inoue, Haruhisa PLoS One Research Article BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. METHODOLOGY/PRINCIPAL FINDINGS: We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. CONCLUSIONS/SIGNIFICANCE: These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation. Public Library of Science 2011-09-30 /pmc/articles/PMC3184175/ /pubmed/21984949 http://dx.doi.org/10.1371/journal.pone.0025788 Text en Yahata et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Yahata, Naoki Asai, Masashi Kitaoka, Shiho Takahashi, Kazutoshi Asaka, Isao Hioki, Hiroyuki Kaneko, Takeshi Maruyama, Kei Saido, Takaomi C. Nakahata, Tatsutoshi Asada, Takashi Yamanaka, Shinya Iwata, Nobuhisa Inoue, Haruhisa Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title | Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title_full | Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title_fullStr | Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title_full_unstemmed | Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title_short | Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease |
title_sort | anti-aβ drug screening platform using human ips cell-derived neurons for the treatment of alzheimer's disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184175/ https://www.ncbi.nlm.nih.gov/pubmed/21984949 http://dx.doi.org/10.1371/journal.pone.0025788 |
work_keys_str_mv | AT yahatanaoki antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT asaimasashi antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT kitaokashiho antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT takahashikazutoshi antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT asakaisao antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT hiokihiroyuki antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT kanekotakeshi antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT maruyamakei antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT saidotakaomic antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT nakahatatatsutoshi antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT asadatakashi antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT yamanakashinya antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT iwatanobuhisa antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease AT inoueharuhisa antiabdrugscreeningplatformusinghumanipscellderivedneuronsforthetreatmentofalzheimersdisease |