Alzheimer’s disease triggers a devastating progressive and insidious dementia that is associated with the deposition of amyloid ß-protein and tau in the brain. The most important proximate cause of symptoms is synaptic failure, which starts long before significant neuronal loss and the onset of clinical dementia. Currently approved drugs for the treatment of Alzheimer’s disease either boost acetylcholine or inhibit NMDA glutamate receptors, but have very limited therapeutic efficacy. We and others recently reported evidence that negative allosteric modulators of metabotropic glutamate (subtype 5, mGlu5) receptor show promise as an alternative strategy to treat the disease. Inhibition of mGlu5 receptors prevents the synaptic and behavioural impairments in animal models of Alzheimer’s disease but these findings need to be extended and validated before testing in patients can begin. Recently, drugs of this class have been, or continue to be, tested in clinical trials for other diseases such as depression and dystonia. The proposed research will evaluate the therapeutic potential of different mGlu5 drugs for Alzheimer’s disease by studying their efficacy against the disruptive actions of patient-derived samples in living animals. We will compare allosteric modulators of the receptor that have the ability to either enhance, block, mimic or reverse the effects of glutamate to varying extents. This will enable us to optimise drug choice for future clinical trials in early Alzheimer’s disease. We believe that results from this study will lead directly to better ways of targeting mGluR receptors in neurology and psychiatry and in particular the development of new potential disease modifying therapies for Alzheimer’s disease.
