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Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila
Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer’s disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into eithe...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026704/ https://www.ncbi.nlm.nih.gov/pubmed/27524482 http://dx.doi.org/10.1016/j.cub.2016.07.017 |
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author | Niccoli, Teresa Cabecinha, Melissa Tillmann, Anna Kerr, Fiona Wong, Chi T. Cardenes, Dalia Vincent, Alec J. Bettedi, Lucia Li, Li Grönke, Sebastian Dols, Jacqueline Partridge, Linda |
author_facet | Niccoli, Teresa Cabecinha, Melissa Tillmann, Anna Kerr, Fiona Wong, Chi T. Cardenes, Dalia Vincent, Alec J. Bettedi, Lucia Li, Li Grönke, Sebastian Dols, Jacqueline Partridge, Linda |
author_sort | Niccoli, Teresa |
collection | PubMed |
description | Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer’s disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into either of these cell types offers therapeutic potential remains unknown. Using an adult-onset Drosophila model of Aβ (amyloid beta) toxicity, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues lifespan, behavioral phenotypes, and neuronal morphology. This amelioration of Aβ toxicity is associated with a reduction in the protein levels of the unfolded protein response (UPR) negative master regulator Grp78 and an increase in the UPR. We further demonstrate that genetic downregulation of Grp78 activity also protects against Aβ toxicity, confirming a causal effect of its alteration on AD-related pathology. Metformin, a drug that stimulates glucose uptake in cells, mimicked these effects, with a concomitant reduction in Grp78 levels and rescue of the shortened lifespan and climbing defects of Aβ-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against Aβ toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD. |
format | Online Article Text |
id | pubmed-5026704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50267042016-09-23 Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila Niccoli, Teresa Cabecinha, Melissa Tillmann, Anna Kerr, Fiona Wong, Chi T. Cardenes, Dalia Vincent, Alec J. Bettedi, Lucia Li, Li Grönke, Sebastian Dols, Jacqueline Partridge, Linda Curr Biol Article Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer’s disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into either of these cell types offers therapeutic potential remains unknown. Using an adult-onset Drosophila model of Aβ (amyloid beta) toxicity, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues lifespan, behavioral phenotypes, and neuronal morphology. This amelioration of Aβ toxicity is associated with a reduction in the protein levels of the unfolded protein response (UPR) negative master regulator Grp78 and an increase in the UPR. We further demonstrate that genetic downregulation of Grp78 activity also protects against Aβ toxicity, confirming a causal effect of its alteration on AD-related pathology. Metformin, a drug that stimulates glucose uptake in cells, mimicked these effects, with a concomitant reduction in Grp78 levels and rescue of the shortened lifespan and climbing defects of Aβ-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against Aβ toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD. Cell Press 2016-09-12 /pmc/articles/PMC5026704/ /pubmed/27524482 http://dx.doi.org/10.1016/j.cub.2016.07.017 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Niccoli, Teresa Cabecinha, Melissa Tillmann, Anna Kerr, Fiona Wong, Chi T. Cardenes, Dalia Vincent, Alec J. Bettedi, Lucia Li, Li Grönke, Sebastian Dols, Jacqueline Partridge, Linda Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title | Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title_full | Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title_fullStr | Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title_full_unstemmed | Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title_short | Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila |
title_sort | increased glucose transport into neurons rescues aβ toxicity in drosophila |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026704/ https://www.ncbi.nlm.nih.gov/pubmed/27524482 http://dx.doi.org/10.1016/j.cub.2016.07.017 |
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