Effect of Abeta on excitotoxic signalling pathways

The NMDA receptor (NMDAR) is a ligand-gated ion channel essential for normal synaptic function and is vital in learning and memory processes. However, when overstimulated, NMDARs are also responsible for a cascade of toxic events, termed “excitotoxicity”, which are triggered by the excessive entry of calcium into the cell through the receptor channel.

Excitotoxicity is implicated in number of neurological disorders including Alzheimer’s disease (AD), in which the Abeta peptide, the major component of plaques in AD brain, has been proposed to enhance the activity of NMDARs. One consequence of excitotoxicity is the increased release of extracellular copper which may feedback on NMDARs to reduce calcium entry to the cell. Our laboratory works with novel compounds that modulate the copper status of cells, and which are neuroprotective in NMDAR excitotoxicity. These compounds appear to act primarily on downstream components in the calcium-signalling pathway rather than at the level of the NMDAR itself, such as the calpain and calcineurin system. This project will further probe the involvement of copper in calcium-mediated excitotoxicity, and determine how Abeta intersects with downstream components of this pathway. Skills learned will include cell culture techniques, western blotting and immunohistochemistry.