Niccoli, T;
Cabecinha, M;
Tillmann, A;
Kerr, F;
Wong, CT;
Cardenes, D;
Vincent, AJ;
... Partridge, L; + view all
(2016)
Increased Glucose Transport into Neurons Rescues A beta Toxicity in Drosophila.
Current Biology
, 26
(17)
pp. 2291-2300.
10.1016/j.cub.2016.07.017.
Preview |
Text
1-s2.0-S0960982216307680-main.pdf Download (1MB) | Preview |
Abstract
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.
| Type: | Article |
|---|---|
| Title: | Increased Glucose Transport into Neurons Rescues A beta Toxicity in Drosophila |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cub.2016.07.017 |
| Publisher version: | http://dx.doi.org/10.1016/j.cub.2016.07.017 |
| Language: | English |
| Additional information: | © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, UNFOLDED-PROTEIN RESPONSE, ALZHEIMERS-DISEASE, MITOCHONDRIAL DYSFUNCTION, COGNITIVE IMPAIRMENT, INSULIN-RESISTANCE, INCREASED RISK, AMYLOID-BETA, Q-SYSTEM, STRESS, METFORMIN |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1503727 |
Archive Staff Only
 |
View Item |
