Prof Myra Conway - UWE Bristol

PhD: 2014 - 2017

Cellular mechanisms leading to Alzheimer’s disease

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

Summary

Previous work in this group has shown that proteins used to produce glutamate (BCAT enzymes) are produced in greater amounts in patients with Alzheimer’s disease. This project will seek to understand if glutamate can be used as a biomarker for Alzheimer’s disease. This may lead to the production of a quick and accurate diagnostic test for Alzheimer’s disease and dementia. A better understanding of the processes responsible for the for onset of Alzheimer’s may lead to the identification of new biomarkers; something which will provide the foundation to develop new strategies for the prevention, treatment and diagnosis of Alzheimer’s disease and related conditions.

What are the aims of this group?

Despite extensive research, the fundamental cellular mechanisms leading to the development of Alzheimer’s disease are poorly understood. As a result treatment of this condition is inadequate, with current medications only being around 30% effective in delaying or relieving the symptoms of Alzheimer’s disease. Prof Conway’s group targets the key areas of Alzheimer’s disease research that remain unanswered, such as understanding the underlying pathogenic mechanisms that govern protein misfolding in the brain and identifying new and novel indicators in the blood that can help to diagnose Alzheimer’s disease.

What have the group found out so far?

Glutamate is a vital neurotransmitter for brain communication, and glutamate dysfunction is a prominent feature of Alzheimer’s disease. Glutamate is synthesised from branched chain amino acids (BCAAs) by BCAT enzymes, and Prof. Conway’s group was the first to show that BCAT expression is hugely increased in Alzheimer’s disease, and this correlates with Alzheimer’s disease severity. This suggests that levels of this protein may be a useful biomarker for tracking Alzheimer’s disease progression, potentially even allowing early detection. Biomarkers are biological properties that can be detected and measured in parts of the body, such as the blood, and are a much needed tool in this area to help with quickly and accurately diagnosing Alzheimer’s disease and dementia.

In another of their most recent studies, Prof Conway’s group aimed to understand how a mechanism responsible for removing unfolded proteins in the brain malfunctions, resulting in the build-up of protein aggregates. Such aggregates are commonly seen in neurodegenerative conditions such as Alzheimer’s disease. Using their current model system, this group have shown that an increased BCAT level in brain cells reduces vesicle formation, a process necessary for optimal clearance of protein aggregates. This leads to an abnormal build-up of protein aggregates, and so may be one of the pathways leading to the degeneration of brain cells in Alzheimer’s disease.

What are they doing next?

The metabolic pathways governed by hBCAT are controlled and regulated through metabolites in the blood. This work is therefore being extended to understand how external influences can be manipulated to regulate protein misfolding in the brain.

Aligned to these projects are biomarker studies, where – in collaboration with Dr Liz Coulthard and Prof Risto Kauppinen – they aim to identify signature profiles to differentiate between patients with mild cognitive impairment that will or will not progress to develop Alzheimer’s disease. Biomarkers are biological properties that can be detected and measured in parts of the body, such as the blood, and are a much needed tool in this area to help with quickly and accurately diagnosing Alzheimer’s disease and dementia.

Additional projects are outlined below.

Scientific title: Regulation of neurotransmitter synthesis in Alzheimer’s disease – potential for dietary supplements to improve cognition

Type of project: PhD studentship, co-supervised by Dr. Carolyn Paul

BCAAs are significantly reduced in conditions involving poor cognition (e.g. dementia), and early work on this project suggests that dietary supplementation can improve cognitive function and cerebral blood flow. Importantly, the reduction in blood BCAAs gives these patients a characteristic amino acid “signature” that may give a readout of Alzheimer’s disease severity. Aligned to this biomarker hypothesis, and in collaboration with Dr. Liz Coulthard and Prof. Risto Kauppinen, Prof. Conway’s group aim to identify these signature profiles in order to differentiate between patients with mild cognitive impairment (MCI) that will or will not progress to develop Alzheimer’s disease. Using neuronal models, the project also aims to better understand the mechanistic link between BCAA levels on neurotransmitter synthesis and cognition.

Scientific title: Unravelling cellular sensing pathways that contribute to Alzheimer's disease pathology

Type of project: Pilot project

Another hallmark of Alzheimer’s disease is protein misfolding, particularly amyloid-β. Prof. Conway’s group have also discovered that – addition to producing glutamate – BCATs are also involved in protein folding. However, under oxidative stress (a process associated with ageing, and enhanced in Alzheimer’s disease), BCAT enzymes can be modified and their protein folding role could be compromised as a result. The subsequent incorrect protein folding leads to aggregates of protein such as amyloid-β and the hallmark amyloid-β plaques found in Alzheimer’s disease. Therefore this may be one of the pathways leading to the degeneration of brain cells in Alzheimer’s disease, and this work is being extended to understand how external influences (i.e. nutrient intake) can be manipulated to regulate protein misfolding in the brain.

Why is it important?

Together, understanding of these pathways will identify possible therapeutic targets and new biomarkers, which will provide the foundation to develop new strategies for the prevention, treatment and diagnosis of Alzheimer’s disease and related conditions. This includes an impact on our understanding of how our nutritional profile can promote healthy aging and slow down the progression of Alzheimer’s disease.

Glossary

Cellular mechanisms – A series of enzyme-controlled processes that occur in cells.
Pathology – The functional manifestations of a disease eg. Symptoms.
Neurotransmitter – Any substance, such as acetylcholine or dopamine, responsible for sending nerve signals across a synapse between two neurons.
Enzymes – A protein responsible for causing a biological chemical reaction to occur quickly.
Biomarker – Biological molecule that can be detected and measured in parts of the body, such as the blood.
Metabolites – Any substance synthesised or modified by a metabolic process.
Cognition – The mental process of knowing, including aspects such as awareness, perception, reasoning, and judgment.
Cerebral – Of or relating to the brain or cerebrum.