title: Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila.
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.
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Niccoli
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cabecinha
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Tillmann
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Kerr
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Chi T
authors.initials: CT
authors.lastname: Wong
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Dalia
authors.initials: D
authors.lastname: Cardenes
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Vincent
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Bettedi
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grönke
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dols
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany. Electronic address: partridge@age.mpg.de.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D051272:Glucose Transporter Type 1; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D008687:Metformin