Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common forms of dementia. In Australia, dementia has now become the second leading cause of death1 where one person is diagnosed every 6 minutes, resulting in over 300,000 Australians currently living with dementia2.
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, leading to nerve cell damage and the eventual onset of dementia. In PD, α-synuclein (α-syn) is thought to be the main culprit, where lack of clearance and overproduction leads to the formation of protein clumps in the brain known as Lewy bodies.3,4
Recently membrane receptors found on microglia cells have been identified as risk factors for AD and PD susceptibility. Studies have found that particular mutations in the extracellular immunoglobulin domain of one of these receptors results in an increased risk of AD and PD development. These mutations lead to suppression of microglial clearance of neurotoxic Aβ and α-syn.5 Our aim is to target this domain with small molecule inhibitors that might confer protection towards AD and PD.
Here we report the crystal structure of this immunoglobulin domain and report the identification of low molecular weight binders from computational virtual screening and confirmed experimentally using Surface Plasmon Resonance. Molecular modelling and computational docking have been utilised to examine ligand binding modes and to identify analogues. Structure-function relationships are currently being analysed using our in-house microglia assay.