Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila

Summary

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.

Highlights

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  Overexpression of glucose transporter Glut1 rescues a Drosophila Aβ toxicity model

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  Glut1 overexpression reduces Grp78 protein levels and induces the UPR

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  A Grp78 dominant-negative mutant also rescues Aβ toxicity in Drosophila

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  Metformin rescues Aβ toxicity and leads to reduced Grp78 expression

Abstract

Niccoli et al. show that overexpression of the glucose transporter Glut1 in neurons rescues Aβ toxicity in a Drosophila Alzheimer’s disease model. This was associated with a reduction in Grp78 levels and induction of the unfolded protein response. This rescue can be mimicked by using metformin, a drug known to induce glucose uptake.