PhD in Dementia Research - Alzheimer’s disease: Understanding the interaction of microglia risk genes

Microglia, the immune cells of the brain, may be protective in Alzheimer’s disease, encircling amyloid plaques, clearing debris and limiting further inflammatory damage. However, microglia can also be damaging in neuroinflammation, promoting inflammatory responses and causing neuronal damage. A weight of genetic evidence, much of which gained through GWAS study has implicated immune pathways in the development of Alzheimer’s disease. How microglia contribute to the development of or protection from Alzheimer’s remains a subject of significant debate. Our aims is to use the human genetic data to guide mechanistic studies of the disease process to elucidate possible therapeutic approaches.
Continuing analysis of the functional consequences of risk and protective variants in human Alzheimer’s disease patients builds a picture from this mounting genetic evidence: defects in or hypofunction forms of activation receptors such as the R47H variant of TREM2 promote Alzheimer’s disease, whereas, defects in/hypofunction of inhibitory receptors, such as CD33 splice variants, protect from Alzheimer’s disease.
This PhD will mechanistically examine evidence of interaction between individual risk alleles leading to significantly enhanced risk of disease. The aim of the study is to understand the interdependence of specific risk alleles and highlight the possibility of adjunctive therapies targeting different ‘arms’ of the immune cells to treat the disease.
The studentship will involve training in lentiviral transduction of cell lines and primary microglia, use of conditional-immortalisation techniques, transcriptomic analysis of cell activation and single cell assessment of cell activation. We have established a bank of reagents to analyse the interaction between specific risk genes, including mutated molecules, chimeric proteins, cellular assays, and gene knockin models of single nucleotide polymorphisms.

Supervisors: Prof Philip Taylor and Dr. Emyr Lloyd-Evans
The research is well-funded with the primary laboratory currently having in excess of £3M in active grant awards.
For further information on the type of research conducted in this project and at the UK Dementia Research Institute at Cardiff, see:
Sims et al., 2017. “Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease.” Nature Genetics 49:1373-1384.
Davies et al., 2014. “The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal” Science 344:645-648.