Project 1 - Glucose Metabolism in Dementia
in collaboration with Adrian Isaacs Laboratory UK DRI
Our brains consume 20% of our body's energy. However, nerve cells can't store energy or use fat as a fuel so they have to generate all their energy from sugar. The brain has complex molecular mechanisms to ensure a constant supply of sugar to nerve cells, but in people with dementia this system breaks down as disease progresses.
We recently discovered that improving sugar delivery helps nerve cells cope with the effects of toxic proteins associated with Alzheimer's Disease. We are now extending this work to another type of dementia: Frontotemporal Dementia (FTD), the second most common early-onset dementia. We use a fly model expressing the most common mutation linked to FTD, a hexanucleotide repeat expansion in the human gene C9orf72 (C9). We are investigating glucose metabolism in this model and investigating whether modulating glucose metabolism can affect C9 toxicity. We will confirm the discoveries from flies in mouse models and in cells donated by FTD patients.
Project 2 - Down Syndrome's and Alzheimer's Disease
in collaboration with Frances Wiseman Laboratory UCL IoN
People with Down Syndrome (DS) are at greater risk of developing early onset Alzheimer's Disease (AD) than the general population. DS is caused by an extra copy of human chromosome 21 (Hsa21), which encodes 234 genes. One of these genes, APP, codes for a protein that is cleaved to form the amyloid plaque (Aβ) that accumulates in the brain in the early stages of AD. How the other genes on Hsa21 affect disease is not yet understood;. Frances Wiseman has recently shown using mouse model that a stretch of 39 Hsa21 orthologues can exacerbate Aβ deposition in the brain. We will now use fly models to pinpoint which of these genes is responsible for this effect. We will go on to investigate the role of this gene in disease, in collaboration with human clinical and genetic data sets collected by LonDownS consortium. This approach will replace the use of mouse Aβ aggregation models to investigates this questions, thus significantly reducing use of animals.