Organisational unit: Research Grouping
Our group is interested in the underlying molecular mechanisms of Alzheimer’s disease pathology. We have a series of linked projects into the production of amyloid, the genetic and environmental influences on this, and the early changes in Alzheimer brain, including changes in growth factors and their receptors.
We are particularly interested in the tyrosine receptors TrkA and TrkB, and their respective ligands nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF and BDNF are neurotrophic factors which support the connections between the cholinergic basal forebrain and the hippocampus. These are brain regions which are responsible for formation of new memories and are adversely affected early in Alzheimer’s disease. BDNF additionally has a vital role in memory formation via facilitation of long term potentiation.
One of our studies has previously shown that only one domain of the Trk receptor is required for binding its ligand (NGF or BDNF); that is the immunoglobulin-like domain closest to the membrane (Ig2). By comparison of the structure of the TrkIg2 domains in complex with their ligands we were able to identify hotspots on the receptors required for specific ligand binding.
By developing this work, in collaboration with other groups across the university, we have used in silico techniques to identify potential binders to the receptors, tested these compounds in vitro, and confirmed the receptor binding sites of the compounds. By these methods we have been able to identify small molecules which bind either TrkA or TrkB at the point of interaction with their ligands. These are being further developed as candidates for drugs as therapeutics for Alzheimer’s disease and pain.