Glucose metabolism as a modulator of Abeta toxicity

Teresa Niccoli (1),  Melissa Cabecinha (1),  Anna Tillmann (1),  Fiona Kerr (1),  Chi T. Wong (1),  Dalia Cardenes (1),  Alec J. Vincent (1), Lucia Bettedi (1),  Li Li (1),  Sebastian Grönke (2), Jacqueline Dols (2) and Linda Partridge (1,2)

(1) Institute of Healthy Ageing, Department of Genetics, Evolution and Environment (GEE), University College London, Darwin Building,
Gower Street, London WC1E 6BT, UK

(2) Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany

Alzheimer’s disease in the most common cause of dementia. 1 in 3 people born today in the UK will develop dementia. Currently there are no cures.  A reduction in glucose metabolism is a prominent feature of the brains of patients with Alzheimer’s disease. 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. Aß (amyloid beta)  protein is thought to be the causative agent of Alzheimer’s disease. Using an adult-onset Drosophila model of Aß 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 an increase in unfolded protein response (UPR), which is responsible for maintaining protein homeostasis within a cell. Metformin, the first line medication for the treatment of type 2 diabetes, stimulates glucose uptake in cells. Treatment of flies with metformin also rescues 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.