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Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector
Efforts to develop drugs for Alzheimer’s disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells carrying the major genetic risk factor apolipoprote...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948154/ https://www.ncbi.nlm.nih.gov/pubmed/29632371 http://dx.doi.org/10.1038/s41591-018-0004-z |
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author | Wang, Chengzhong Najm, Ramsey Xu, Qin Jeong, Dah-eun Walker, David Balestra, Maureen E. Yoon, Seo Yeon Yuan, Heidi Li, Gang Miller, Zachary A. Miller, Bruce L. Malloy, Mary J. Huang, Yadong |
author_facet | Wang, Chengzhong Najm, Ramsey Xu, Qin Jeong, Dah-eun Walker, David Balestra, Maureen E. Yoon, Seo Yeon Yuan, Heidi Li, Gang Miller, Zachary A. Miller, Bruce L. Malloy, Mary J. Huang, Yadong |
author_sort | Wang, Chengzhong |
collection | PubMed |
description | Efforts to develop drugs for Alzheimer’s disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells carrying the major genetic risk factor apolipoprotein E4 (apoE4), we demonstrate that apoE4 neurons have higher levels of tau phosphorylation unrelated to their increased Aβ production and displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting apoE4 to apoE3 by gene editing rescued these phenotypes, indicating the specific effects of apoE4. Neurons lacking apoE behaved like those expressing apoE3, and introducing apoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from apoE4. Treating apoE4 neurons with a small-molecule structure corrector ameliorated the detrimental effects, providing a proof of concept that correcting the pathogenic conformation of apoE4 is a viable therapeutic approach for apoE4-related AD. |
format | Online Article Text |
id | pubmed-5948154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-59481542018-10-09 Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector Wang, Chengzhong Najm, Ramsey Xu, Qin Jeong, Dah-eun Walker, David Balestra, Maureen E. Yoon, Seo Yeon Yuan, Heidi Li, Gang Miller, Zachary A. Miller, Bruce L. Malloy, Mary J. Huang, Yadong Nat Med Article Efforts to develop drugs for Alzheimer’s disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells carrying the major genetic risk factor apolipoprotein E4 (apoE4), we demonstrate that apoE4 neurons have higher levels of tau phosphorylation unrelated to their increased Aβ production and displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting apoE4 to apoE3 by gene editing rescued these phenotypes, indicating the specific effects of apoE4. Neurons lacking apoE behaved like those expressing apoE3, and introducing apoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from apoE4. Treating apoE4 neurons with a small-molecule structure corrector ameliorated the detrimental effects, providing a proof of concept that correcting the pathogenic conformation of apoE4 is a viable therapeutic approach for apoE4-related AD. 2018-04-09 2018-05 /pmc/articles/PMC5948154/ /pubmed/29632371 http://dx.doi.org/10.1038/s41591-018-0004-z Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Wang, Chengzhong Najm, Ramsey Xu, Qin Jeong, Dah-eun Walker, David Balestra, Maureen E. Yoon, Seo Yeon Yuan, Heidi Li, Gang Miller, Zachary A. Miller, Bruce L. Malloy, Mary J. Huang, Yadong Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title | Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title_full | Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title_fullStr | Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title_full_unstemmed | Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title_short | Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by a Small-Molecule Structure Corrector |
title_sort | gain of toxic apolipoprotein e4 effects in human ipsc-derived neurons is ameliorated by a small-molecule structure corrector |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948154/ https://www.ncbi.nlm.nih.gov/pubmed/29632371 http://dx.doi.org/10.1038/s41591-018-0004-z |
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