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- Title
Anti-Aβ Drug Screening Platform Using Human iPS Cell- Derived Neurons for the Treatment of Alzheimer's Disease.
- Authors
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
- Abstract
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 b peptide (Ab), which is produced from amyloid precursor protein by b- and c-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, b-secretase, and c-secretase components, and were capable of secreting Ab into the conditioned media. Ab production was inhibited by b-secretase inhibitor, c-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 (Ab surge) and drastic decline of Ab production. Conclusions/Significance: These results indicate that the hiPS cell-derived neuronal cells express functional b- and csecretases involved in Ab production; however, anti-Ab drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.
- Subjects
DRUG use testing; ALZHEIMER'S disease treatment; NEURODEGENERATION; AMYLOID beta-protein precursor; PRESENILE dementia; CYTOLOGICAL research; DISEASE susceptibility
- Publication
PLoS ONE, 2011, Vol 6, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0025788