Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common forms of dementia. It is currently thought that AD results from an imbalance of production and clearance of amyloid-β (Aβ) peptide, which forms plaques in the AD-affected brain. The formation of Lewy bodies, clumps of α-synuclein (α-syn) protein, in regions of the brain that control movement is accountable for the onset of PD.
Resident macrophages in the brain known as microglia are responsible for clearing toxic species in the brain, including Aβ and α-syn. Recently, immunoglobulin membrane receptors found on microglia cells have been identified as risk factors for AD and PD susceptibility. Genetic studies have found certain mutations located in the extracellular ligand-binding domains of these receptors can decrease or increase the risk of AD and PD development. However the signaling mechanisms of these receptors is poorly understood. The aim of my PhD work is to investigate the structure and function of these receptors, and how they can be targeted for AD and PD therapeutics.
Preliminary experiments include solving the 3D atomic structure of the ligand-binding domain of one of these receptors by X-ray crystallography, and screening for potential ligands with computational virtual screening. Co-crystallisation trials are currently underway to confirm ligand-binding modes. Biophysical and fluorescence cell-based techniques are currently being employed to examine signaling mechanisms.
Understanding the structure and function of these receptors will help us to target reactivation of microglial clearance of Aβ and α-syn, reducing their accumulation and propagation.