Summary
Age is currently the biggest risk factor for developing Alzheimer’s disease. It is not well understood how ageing impacts hallmark Tau and amyloid pathology in the brain and neuronal function. The PhD student will investigate how age related shifts in mitochondrial and peroxisomal metabolism impact the behavior and neurodegeneration seen in Drosophila models of Alzheimer’s disease. The student will learn cutting edge imaging techniques and bioinformatic approaches.
Project Description
The number of people with dementia in the UK is forecast to increase to 1,000,000 by 2025 and 1,590,000 by 2040 and this trend is echoed globally. Over the age of 65 the risk of developing Alzheimer's disease (AD) increases almost exponentially with age. The molecular mechanisms controlling age-related risk are not well understood. Dysfunction of energy generating organelle, the mitochondrion in neurons with age is well established, and growing evidence attributes this decline to loss of mitochondrial DNA (mtDNA) integrity, dynamics and physiology. Oxidative stress and metabolism shifts due to mitochondrial failure may drive increased amyloidogenic processing, contributing to pathology and may lead to irreversibly lipid oxidation and cellular damage. There is also growing evidence that the metabolic process of β-oxidation, which starts in the peroxisome compartment of cells is severely effected in AD. This process is essential to fuel oxidative phosphorylation in the mitochondria. The PhD student will therefore investigate whether improving peroxisomal and mitochondrial function in model systems may delay AD related changes.
Aim 1: The student will first learn to use the fruit fly Drosophila to determine the effect of inducing mtDNA mutations and other mitochondrial abnormalities, on the pathology and behavioural phenotypes of Drosophila AD models. Both ‘humanised’ Tau (mutant and wild-type) and amyloid beta 42 (AB) transgenic models will be used throughout. We also have a large tool set to enable us to determine mitochondrial and peroxisomal health in vivo at different ages using cutting edge fluorescent imaging techniques.
Aim 2: The PhD student will have the opportunity to learn how to generate and analyse large bioinformatic data sets. Dissected brain samples from our AD models with and without mitochondrial dysfunction will be processed for untargeted lipidomic and metabolomic analysis and dysregulated species mapped into molecular pathways. Using these data, we will then genetically inhibit or overexpress several select candidate enzymes using commercially available Drosophila libraries, with the aim of improving AD phenotypes in flies that maybe specifically related to Tau or AB.
Aim 3: The student will also have the opportunity to investigate a defined lipid pathway relevant to AD. Cortical accumulation of saturated very long chain fatty acids (VLCFAs), substrates for peroxisomal β-oxidation, are increased in AD patient brains and animal models. Peroxisomal function is tightly linked to mitochondrial function since the product of β-oxidation, acetyl-CoA, is required to fuel Krebs Cycle and ultimately generate ATP. The student will investigate whether enhanced peroxisome lipid transportation in vivo will improve AD phenotypes. This will require molecular cloning techniques to produce a new’ humanised’ transgenic animal expressing ACDB5, which would be of interest to the Drosophila and metabolism communities.
These aims set out the broad experiments for the project, however our lab activity encourages and equips PhD students to drive the direction of the project based on their initial discoveries. Age is currently the biggest risk factor for developing AD. Understanding the mechanisms behind this process may open-the-door to therapeutics targeted to alter a particular metabolic or lipidomic pathway.
