PhD in Dementia Research - The role of Alzheimer’s risk genes in glial function using Drosophila

Glial dysfunction is likely to be a significant contributing factor in the pathogenesis of Alzheimer’s disease (AD) through several mechanisms1. Dysregulated microglial cells can excessively eliminate neuronal synapses in the brain of AD patients and this loss strongly correlates with cognitive decline. Phagocytosis by glial cells is also required for efficient clearance of amyloid beta (AB) aggregates, which accumulate during disease progression and failure to clear this build-up may also negatively impact neuronal survival. Genome Wide Association Studies have recently identified a number of AD risk genes related to neuro-immune interactions2,3 which may influence these essential glial processes.
In this PhD project, the student will determine whether conserved AD risk genes influence glial phagocytosis and/or synapse elimination by conducting reverse genetic screens using Drosophila. Orthologues of AD risk genes can be each knocked down specifically in neurons, glia or both (depending on the gene), using commercially available RNAi, and changes to the stereotyped synaptic terminals analysed in the aged brain. The student will also knock down/ overexpress AD risk gene orthologues in glia in a model where AB is expressed in neurons and determine the effect on disease progression. Once candidate genes have been identified, the underlying cell biology consequences will be determined through the use of genetic encoded tools for use in vivo (e.g. GCaMPs, fluorescent organelle labels etc.) and molecular pathways determined by targeted epistasis experiments. As required we will utilize CRISPR/Cas9 technology to generate new mutants of AD risk genes to complement RNAi studies.
The PhD student will be situated within the Dementia Research Institute (DRI) and will have access to specialised fly facilities and cutting edge equipment within a highly collaborative environment. New data generated on AD risk genes will form part of the UK DRI mission to tackle the huge challenge of dementia.