Lead Investigator: Dr Gayle Doherty (nee Middleton)
Institution: University of St Andrews
Grant type: Research Fellowship
Grant amount: £146,689
Start date: April 2008
Completion date: January 2013
Scientific Title: Consequences of hyperhomocysteinemia for Alzheimer's Disease: a genetic, proteomic and cellular approach.
What was the project, and what did the researchers do?
This project aimed to investigate homocysteine and its role in the development of Alzheimer's disease.
Homocysteine is a natural substance that we all make within our bodies. However, there are a number of reasons why levels of this substance can increase in the blood, such as diet, lifestyle and ageing itself. It has been established that people with high levels of homocysteine in their blood have double the risk of developing Alzheimer's disease. This project aimed to uncover the changes that occur within nerve cells that may account for this risk.
There were two approaches to this research. In one, Dr Doherty looked at mice that have high levels of homocysteine in their blood and determined what changes could be seen within their cells. This portion of the work identified a number of changes linked to structures in the cell known as mitochondria. Mitochondria make energy for cells and so this suggests that homocysteine might lead to cells having insufficient energy to operate and survive properly.
In the second approach, Dr Doherty looked at proteins that other researchers have identified as being important in Alzheimer's disease and she asked whether homocysteine influences these proteins.
What were the key results, and how will this help in the fight against dementia?
Dr Doherty discovered that homocysteine can affect a number of proteins that have been linked to Alzheimer's disease.
She has looked at ways of moderating the effects of these proteins in brain cells grown in the lab in order to prevent homocysteine killing neurones (nerve cells). It was found that if cells can be made to not respond to one of the tested proteins, endothelial nitic oxide synthase (eNOS), in a certain way, these neurones can be stopped from dying.
Dr Doherty also found that if another protein, called monoamine oxidase type B is blocked, then neurones can again be prevented from dying. Monoamine oxidase is an enzyme (responsible for 'breaking down' other proteins) found on mitochondria, confirming that they play a role in cell death in relation to high homocysteine levels.
The findings that Dr Doherty has produced to date go some way in explaining why elevated levels of homocysteine increase your risk of developing Alzheimer's disease. Crucially, she has uncovered some processes that could be targeted to prevent this increased risk. However, there is much more work to be done.
What happened next? Future work and additional grants
As a result of attaining the Alzheimer's Society Research Fellowship, and the research publications and directions that have arisen from holding it, Dr Doherty has been awarded a lectureship at St Andrews University in the newly-formed School of Psychology and Neuroscience.
The Fellowship opened up many more research leads than it was possible to pursue. These will be used to provide research topics for future funding applications investigating not only how homocysteine is linked to Alzheimer's disease but also what we can do to prevent or slow down the progression to Alzheimer's disease in hyperhomocysteinemic individuals.
How were people told about the results? Conferences and publications
Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ. & Harvey J. 2013. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid beta. Neurobiol. Aging, 34(1):226-37
Invited review articles:
Doherty GH, 2011. Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Neurosci Bull. 27, 6, 366-82.
Doherty GH, 2011. Obesity and the ageing brain: could leptin play a role in neurodegeneration? Current Gerontol Ger Res., Article ID: 708154, DOI:10.1155/2011/708154
Doherty GH, 2008. Boom and Bust for Homocysteine? CNS Agents in Med Chem. 8, 2, p. 107-120.
Doherty GH, 2011. How can we prevent neuronal apoptosis? In: Apoptosis Research Advances. Schmid, CJ. & Wolde JL. (eds.) Nova Science Publishers: ISBN 978-1-61324-633-7
Doherty GH, 2011. Leptin: a novel therapeutic target in the fight against neurodegeneration? In: Leptin: Hormonal functions, dysfunctions and clinical uses. Hemling, R. & Belkin, A. (eds.). Nova Science Publishers: ISBN 978-1-61122-891-5
Lindsay A, McVee J. & Doherty GH, 2010. Can anti-inflammatory treatments be of benefit to Alzheimer's Disease sufferers? In: Metabolic Influences on Neurological Disorders. Doherty GH. (ed.). Transworld research network: ISBN 978-81-7895-481-3
Doherty GH, 2010. Metabolic influences on neurological disorders: Focus on homocysteine in Alzheimer's Disease. In: Metabolic influences on neurological disorders. Doherty GH. (ed.). Transworld research network: ISBN 978-81-7895-481-3
Doherty, GH. Implications of homocysteine for Alzheimer’s Disease. In Homocysteine: Structure, Biosynthesis and Health Implications, Nova Publishers.
- Scottish Neuroscience Group, Gayle Helane Doherty (Invited speaker), Aug-2012
- Alzheimer's Research Trust Network Meeting, Gayle Helane Doherty (Invited speaker), Sep-2009
This project was generously supported by the Henry Smith Charity.