Scientist Profile Directory

Accumulation of soluble amyloid beta oligomers (AβOs) is closely linked to cognitive decline in Alzheimer’s disease (AD). Our research is focused on identifying molecular mechanisms through which AβOs disrupt the function and plasticity of glutamate excitatory synapses and thus precipitate cognitive decline. AβOs are known to provoke accumulation of glutamate, associated with excitotoxic stimulation of Ca2+ permeable NMDA-type glutamate receptors (NMDARs). Notably, partial block of NMDARs is responsible for the beneficial (though modest) response in patients treated with memantine/Ebixa, a “weak” NMDAR blocker. As more potent NMDAR blockers are associated with intolerable side effects, our research seeks to identify downstream effectors of NMDAR-initiated excitotoxic cascades. To this end, our research has identified distinct signalling cascades that link NMDARs to the activation of Ca2+ permeable non-selective cation channels TRPM2 and Pannexin 1 (Panx1). Moreover, AβO accumulation stimulates their aberrant activation, which in turn contributes to amyloid-induced impairment of synaptic transmission and plasticity. An extension of this work seeks to identify the consequence of aberrant TRPM2 and Panx1 activity 1) in synaptic compartments vulnerable to injury in neurodegeneration as well as 2) in microglia, a cellular compartment in which altered channel activation may stimulate synaptotoxic responses.