Exploring the therapeutic potential of blocking the metabotropic glutamate receptor in the Alzheimer’s disease brain (PhD Studentship)

See glossary at bottom of page for definition of underlined words.

Summary

Adequate signalling between the synapses of nerve cells in the brain is believed to be responsible for memory and other cognitive functions. This project seeks to understand if activation of a specific G protein-coupled synaptic receptor (known as mGluR5) has a harmful impact on the signalling between nerve cells. Analysis of mGluR5 levels in Alzheimer’s brain tissue will be compared to normal brain tissue. The effect of mGluR5 on other synaptic molecules will also be analysed. Understanding the roles of synaptic proteins in Alzheimer’s disease is vitally important in developing a therapeutic treatment for the disease.

What do we already know?

Memory and other cognitive functions are thought to rely on the connections between nerve cells (neurons) in the brain. These interfaces between neurons, termed synapses, are the primary means by which neurons communicate with one another. Electrochemical signals are sensed by receptors, and signals are transmitted across vast networks of neurons. One important group of synaptic receptors, G protein-coupled receptors, have previously been associated with many different disease states. Indeed, around 40% of all drugs currently employed to treat diseases target these receptors. Existing evidence suggests that the metabotropic glutamate receptor subtype 5 (mGluR5), a type of G protein-coupled receptor, might play an important role in the pathogenesis of Alzheimer’s disease. However, this hypothesis has not been fully explored.

What is this project trying to find out?

This project aims to determine whether mGluR5 can serve as a possible therapeutic target for symptom modification in Alzheimer’s disease. Recent work we have undertaken suggests that the abnormal activation of mGluR5, such that might occur in certain stages of Alzheimer’s disease, has a deleterious impact on molecular signaling and function at the synapse.

How is this being done?

Two approaches are being taken to address this issue. Firstly, human cell lines are being used to explore the relationships between mGluR5 and other synaptic molecules. Here we are examining the interactions between mGluR5 and other glutamate receptors, as well as various intracellular signaling cascades. Secondly, using human postmortem brain tissue from Alzheimer’s disease and non-disease patients, we are determining the exact status of mGluR5 in the disease brain, at the genetic and protein levels.

Why is it important?

Developing our understanding of the roles of synaptic proteins (and in this case mGluR5 specifically) in the pathology of Alzheimer’s disease will be crucial in directing the development of novel therapeutic interventions for the disease.

Glossary

Cognitive functions – Functions that are related to cognition (the mental process of knowing).
Electrochemical signals – Signals which are sent via the nerve cells are considered electrochemical in nature. Chemical as they are transmitted via small chemicals (known as neurotransmitters) and electrical as each neuron makes up a part of an overall circuit.
Receptors – A protein or cell component that is specifically designed to bind a small molecule or protein to elicit an effect.
G protein
– A family of proteins involved in the transfer of signals from outside the cell to the inside.
Pathogenesis
– The development of the symptoms of a disease.
Therapeutic target – A therapeutic target is the protein / receptor that a pharmaceutical drug will bind to in order to cause its effect.
Therapeutic intervention – A treatment which is designed to reduce or reverse the symptoms of a disease.
Synaptic proteins – Proteins which are involved in the transmission of electrical signals via the synaptic gap of nerve cells.
Pathology – The functional manifestations of a disease eg. Symptoms.

Further information

Please click here for more information about the work of Professor Kei Cho