Exploring the therapeutic potential of blocking the metabotropic glutamate receptor in the Alzheimer’s disease brain

Scientific title: Negative allosteric modulation of mGluR5 receptor: biological validation of asymptomatic modifier for dementia

Type of project: PhD studentship – Celia Martínez-Pérez (pictured above), co-supervised by Professor Kei Cho and Dr Daniel Whitcomb

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 aberrant 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.

Further information

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