Gamma secretase modulators and BACE inhibitors reduce Aß production without altering gene expression in Alzheimer's disease iPSC-derived neurons and mice.
Mol Cell Neurosci
; 100: 103392, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31381983
ABSTRACT
In drug discovery, as well as in the study of disease biology, it is fundamental to develop models that recapitulate aspects of a disorder, in order to understand the pathology and test therapeutic approaches. Patient-derived induced pluripotent stem cells (iPSCs) offer the potential of obtaining tissue-specific cells with a given human genotype. Here we derived neural cultures from Alzheimer's disease patient iPSCs and characterized their response to three classes of compounds that reduce the production of Aß42, a major driving force of this pathology. We characterized their effect on the cells, looking at Tau proteostasis and gene expression changes by RNAseq. ß-secretase inhibitor and γ-secretase modulators left the transcriptional balance of the cells virtually unaffected, while γ-secretase inhibitors caused drastic gene expression changes due to Notch inhibition. We observed similar effects in vivo, treating mice with the same compound classes. Our results show that ß-secretase inhibitors and γ-secretase modulators are attractive candidates for modulating Aß production in Alzheimer's disease. Moreover, we demonstrate that the response to compounds obtained with iPSC-derived neurons is similar to the one observable in vivo.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Secretases da Proteína Precursora do Amiloide
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Células-Tronco Pluripotentes Induzidas
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Doença de Alzheimer
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Neurônios
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Mol Cell Neurosci
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
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