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

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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)R806-R809
Number of pages4
JournalCurrent Biology
Volume26
Issue number18
Early online date11 Aug 2016
DOIs
Publication statusPublished - Sep 2016

Fingerprint

Drosophila
Neurons
Toxicity
Alzheimer disease
neurons
toxicity
unfolded protein response
Unfolded Protein Response
Glucose
glucose transporters
Alzheimer Disease
glucose
Facilitative Glucose Transport Proteins
metformin
uptake mechanisms
Protein Unfolding
therapeutics
Proteins
blood-brain barrier
Metformin

Keywords

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

Cite this

Niccoli, Teresa ; Cabecinha, Melissa ; Tillmann, Anna ; Kerr, Fiona ; Wong, Chi T. ; Cardenes, Dalia ; Vincent, Alec J. ; Bettedi, Lucia ; Li, Li ; Gronke, Sebastian ; Dols, Jacqueline ; Partridge, Linda. / Increased glucose transport into neurons rescues Aß toxicity in Drosophila. In: Current Biology. 2016 ; Vol. 26, No. 18. pp. R806-R809.
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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 A{\ss} (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 A{\ss} 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 A{\ss} 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 A{\ss}-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against A{\ss} toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD.",
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Niccoli, T, Cabecinha, M, Tillmann, A, Kerr, F, Wong, CT, Cardenes, D, Vincent, AJ, Bettedi, L, Li, L, Gronke, S, Dols, J & Partridge, L 2016, 'Increased glucose transport into neurons rescues Aß toxicity in Drosophila', Current Biology, vol. 26, no. 18, pp. R806-R809. https://doi.org/10.1016/j.cub.2016.07.017, https://doi.org/10.1016/j.cub.2016.09.018

Increased glucose transport into neurons rescues Aß toxicity in Drosophila. / Niccoli, Teresa; Cabecinha, Melissa; Tillmann, Anna; Kerr, Fiona; Wong, Chi T.; Cardenes, Dalia; Vincent, Alec J. ; Bettedi, Lucia; Li, Li; Gronke, Sebastian; Dols, Jacqueline; Partridge, Linda.

In: Current Biology, Vol. 26, No. 18, 09.2016, p. R806-R809.

Research output: Contribution to journalArticle

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T1 - Increased glucose transport into neurons rescues Aß toxicity in Drosophila

AU - Niccoli, Teresa

AU - Cabecinha, Melissa

AU - Tillmann, Anna

AU - Kerr, Fiona

AU - Wong, Chi T.

AU - Cardenes, Dalia

AU - Vincent, Alec J.

AU - Bettedi, Lucia

AU - Li, Li

AU - Gronke, Sebastian

AU - Dols, Jacqueline

AU - Partridge, Linda

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KW - neurons

KW - Drosophila

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