Abstract
| Original language | English |
|---|---|
| Pages (from-to) | R806-R809 |
| Number of pages | 4 |
| Journal | Current Biology |
| Volume | 26 |
| Issue number | 18 |
| Early online date | 11 Aug 2016 |
| DOIs | |
| Publication status | Published - Sep 2016 |
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Keywords
- glucose hypometabolism
- neurons
- Drosophila
- Alzheimer’s disease
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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 journal › Article
TY - JOUR
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
N1 - Acceptance from journal webpage OA article funded by Wellcome Trust
PY - 2016/9
Y1 - 2016/9
N2 - 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.
AB - 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.
KW - glucose hypometabolism
KW - neurons
KW - Drosophila
KW - Alzheimer’s disease
U2 - 10.1016/j.cub.2016.07.017
DO - 10.1016/j.cub.2016.07.017
M3 - Article
VL - 26
SP - R806-R809
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 18
ER -