Research Output

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 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

  • Date:

    01 August 2016

  • Publication Status:

    Published

  • Publisher

    Elsevier BV

  • DOI:

    10.1016/j.cub.2016.07.017

  • Cross Ref:

    S0960982216307680

  • ISSN:

    0960-9822

  • Library of Congress:

    QH301 Biology

  • Dewey Decimal Classification:

    572 Biochemistry

Citation

Niccoli, T., Cabecinha, M., Tillmann, A., Kerr, F., Wong, C., Cardenes, D., …Partridge, L. (2016). Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila. Current Biology. 26(17), 2291-2300. doi:10.1016/j.cub.2016.07.017. ISSN 0960-9822

Authors

Keywords

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences(all)

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