Increased glucose transport into neurons rescues Aß toxicity in Drosophila

Teresa Niccoli, Melissa Cabecinha, Anna Tillmann, Fiona Kerr, Chi T. Wong, Dalia Cardenes, Alec J. Vincent, Lucia Bettedi, Li Li, Sebastian Gronke, Jacqueline Dols, Linda Partridge*

*Corresponding author for this work

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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 Aß (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 Aß 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 Aß 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 Aß-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against Aß toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD.
Original languageEnglish
Pages (from-to)2291-2300
Number of pages10
JournalCurrent Biology
Volume26
Issue number17
Early online date11 Aug 2016
DOIs
Publication statusPublished - 12 Sep 2016

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Keywords

  • glucose hypometabolism
  • neurons
  • Drosophila
  • Alzheimer’s disease

Cite this

Niccoli, T., Cabecinha, M., Tillmann, A., Kerr, F., Wong, C. T., Cardenes, D., Vincent, A. J., Bettedi, L., Li, L., Gronke, S., Dols, J., & Partridge, L. (2016). Increased glucose transport into neurons rescues Aß toxicity in Drosophila. Current Biology, 26(17), 2291-2300. https://doi.org/10.1016/j.cub.2016.07.017