Dementia is the most common cause of death in the UK and it is estimated that one in three people born in the UK today will develop some form of this disease. Globally, the number of people living with dementia will increase from 46.8m in 2015 to 131.5m in 2050, a 281% increase. Currently there are no effective treatments.
Dementia progression is commonly associated with a reduction in glucose metabolism in the brain. The brain is a highly metabolically active organ, using about 20% of the energy consumed by the human body. However, neurons lack energy storage mechanisms and therefore rely on a continuous supply of glucose to fuel their high energy requirements.
In Alzheimer’s disease (AD), the most common form of dementia, a drop in glucose metabolism precedes the onset of clinical symptoms, worsens with disease progression, and mirrors the pattern of brain degeneration. Mechanistically this may be linked to a reduction in the expression of glucose transporters in the brain.
However, whether increasing glucose transport offers therapeutic potential remains unknown. Using a fruit-fly model of Alzheimer’s disease, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues a number of pathologies. Metformin, a drug known to stimulates glucose uptake in cells, mimicked these effects. This rescue was mediated by the Unfolded Protein Response (UPR), a cellular process designed to remove misfolded proteins.
Our findings demonstrate a protective effect of increased neuronal uptake of glucose against AD associated toxicity.