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Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer’s disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that...

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Autores principales: Young, Jessica E., Fong, Lauren K., Frankowski, Harald, Petsko, Gregory A., Small, Scott A., Goldstein, Lawrence S.B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919412/
https://www.ncbi.nlm.nih.gov/pubmed/29503090
http://dx.doi.org/10.1016/j.stemcr.2018.01.031
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author Young, Jessica E.
Fong, Lauren K.
Frankowski, Harald
Petsko, Gregory A.
Small, Scott A.
Goldstein, Lawrence S.B.
author_facet Young, Jessica E.
Fong, Lauren K.
Frankowski, Harald
Petsko, Gregory A.
Small, Scott A.
Goldstein, Lawrence S.B.
author_sort Young, Jessica E.
collection PubMed
description Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer’s disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system.
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spelling pubmed-59194122018-04-27 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein Young, Jessica E. Fong, Lauren K. Frankowski, Harald Petsko, Gregory A. Small, Scott A. Goldstein, Lawrence S.B. Stem Cell Reports Article Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer’s disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system. Elsevier 2018-03-01 /pmc/articles/PMC5919412/ /pubmed/29503090 http://dx.doi.org/10.1016/j.stemcr.2018.01.031 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Young, Jessica E.
Fong, Lauren K.
Frankowski, Harald
Petsko, Gregory A.
Small, Scott A.
Goldstein, Lawrence S.B.
Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title_full Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title_fullStr Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title_full_unstemmed Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title_short Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein
title_sort stabilizing the retromer complex in a human stem cell model of alzheimer’s disease reduces tau phosphorylation independently of amyloid precursor protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919412/
https://www.ncbi.nlm.nih.gov/pubmed/29503090
http://dx.doi.org/10.1016/j.stemcr.2018.01.031
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