Research into dementia is carried out all over the world but we are lucky in the South West to have a large group of scientists, clinicians and psychologists working in the Bristol area on different aspects of dementia research.
BRACE has no particular strategic approach to the type and scope of projects it will consider for funding except that they should be of the highest scientific quality and address an area of research that would ultimately lead to improvements in diagnosis, treatment or quality of life for sufferers of dementing conditions.
Applications are invited from researchers in the region on a regular basis, as funds allow. Each research project is assessed for suitability by the Trustees Scientific Advisory Committee (SAC) chaired by Professor Stephen Lisney. Each project is then sent out for peer review to experts in the field of research of the project. The SAC then makes its recommendations for funding to the Trustees who approve funding.
Current Research Projects
Some of the current project areas that we support are:
- The Neurotrophins - balance between life and death Dr Shelley Allen and her group are working to understand the molecular changes underlying Alzheimer's disease, which is a necessary path towards the development of novel therapeutics. Their BRACE-funded research investigates and identifies changes which occur in the regions of the brain which are affected very early in Alzheimer's disease.
Following the group's work which showed an increase in the enzyme which produces amyloid (beta-secretase) in Alzheimer's disease brain, they are looking at why this enzyme increases and the effects that 'in house' peptide inhibitors have on this enzyme.
In addition they are interested in a small group of 'cholinergic' cells, which connect and communicate with cells in another brain structure, called the hippocampus. Together these brain areas are crucial for the formation of memories, and it is their degeneration which results in the memory and attention problems associated with Alzheimer's disease. The cholinergic cells and those of the hippocampus require a protein, called BDNF or brain-derived neurotrophic factor to stay healthy. Levels of BDNF are much reduced in Alzheimer's brain. The cholinergic cells also require another protein called nerve growth factor (NGF) for their maintenance. NGF is present in two forms: proNGF and 'mature' NGF. These interact with other proteins called 'receptors' on the surface of cholinergic cells. Mature NGF keeps cholinergic cells alive; whereas evidence suggests that proNGF may lead to cell death. As there is an increase in proNGF in Alzheimer's disease brain, the group is trying to understand whether a harmful imbalance in proNGF/mature NGF levels is causing early degeneration of the cholinergic cells, and also how this may relate to the changes seen in BDNF levels.
The group is working, not only to understand the basic underlying mechanisms involved, but also to 'redress the balance', and one of their ongoing projects is to produce a drug which will mimic the benefits of NGF and support the cholinergic cells.
- Neurifibrillary tangles and TGFß signalling in Alzheimer's disease Dr Katy Chalmers is working with Dr Patrick Kehoe and Professor Seth Love in the Dementia Research Group. Her work is addressing an important area of how functions of the genes that protect the brain are impaired in Alzheimer's disease by the abnormal binding of one particular protein, (Smad3) in abnormal neurons. The TGFß signalling pathway is involved in protecting the brain cells, reducing inflammation and providing a network of molecules which support the brain cells so that they can function. One of the key proteins in the pathway, pSmad3 is found to be sequestered in neurofibrillary tangles, thus potentially preventing it from carrying out its normal functions that would provide protection to brain cells. If this project can show exactly what is taking place, therapies that counteract the binding may be possible, with significant impact on the way Alzheimer's disease is treated. This is at the forefront of international research and the availability of the material from the South West Dementia Brain Bank means that Katy has access to the relevant resources to carry out this project.
- The role of caveolins in the processing of amyloid precursor protein Dr Emma Kidd and Dr Rhian Thomas (University of Cardiff).
Evidence is accumulating to suggest that changes in endocytosis may be involved in the pathogenesis of Alzheimer’s disease (AD). Dr Kidd’s group is currently investigating the importance of a number of endocytic proteins involved in clathrin- and non-clathrin-dependent endocytosis in the processing of proteins important for AD. In particular, there is growing evidence to link the caveolin proteins involved in non-clathrin-dependent endocytosis to various aspects of AD, as higher levels have been found in AD brains than in non-AD brains. However, attempts to relate the relevance of this finding to the processing of amyloid precursor protein (APP) have produced conflicting results.
Data from a previous BRACE-funded grant to Dr Kidd showed that decreasing the expression of caveolin-1 in immortalised cells increased amyloid-β (Aβ) production and a concomitant up-regulation of other related proteins, caveolin-3 and flotillin-1 was also seen. The current project will extend this work and aims to understand the mechanisms underlying these findings and to emphasise the importance of lipid raft proteins to the processing of APP.
During the project, the expression of flotillins will be altered to investigate further the functional interaction between these proteins and their effects on APP processing. Global disruption of lipid rafts will then be carried out to compare the effects of manipulating lipid rafts and altering specific proteins on Aβ production as caveolins are found elsewhere in cells and have other functions. Finally, experiments will investigate how lipid raft proteins modulate APP processing in more physiologically relevant primary neurones.
It is anticipated that this project will enhance understanding of the role of caveolins and lipid rafts in AD pathogenesis and will also provide important information regarding their effects on APP processing and production of Aβ. Currently it is not clear whether the higher levels of Aβ found in AD lead to the observed increases in caveolins or whether increased levels of caveolin represent an earlier causative stage in the disease process. Ultimately, the results should enhance knowledge of the disease process and highlight future therapeutic targets.
Some of the data from our research into caveolins and their potential role in Alzheimer's disease were presented at the 5th Conference on Advances in Molecular Mechanisms underlying Neurological Disorders in Bath in June 2013. The abstract can be viewed using this link.
- The BCAT proteins and their potential role in the pathogenesis of Alzheimer's disease Dr Myra Conway (University of the West of England) leads a project that aims to decipher how alterations to key metabolic mechanisms in the brain can contribute to the pathogenesis of Alzheimer's disease (AD). An understanding of how these pathways are altered can highlight potential drug targets for the development of new and novel therapies to slow down or prevent the progression of AD.
Through funding from BRACE the role of the branched chain aminotransferase proteins (BCAT) in contributing to the pathogenesis of AD will be investigated. The human branched chain aminotransferase enzymes are strategically located in the axon and nerve terminals of glutamatergic neurons, where they are responsible for the production of 30% of glutamate in the brain. In health glutamate plays a dominant role in facilitating learning and memory. However, when levels of glutamate rise, as seen in patients with Alzheimer's disease, there is a direct increased in intracellular calcium leading to amplification in cell signalling and oxidative stress, ultimately contributing to Aβ plaque formation and destruction of neuronal integrity and cell death.
Preliminary studies from Dr Conway's group have identified a significant increase in the expression of the BCAT proteins in the brains of patients with AD relative to control patients. As the BCAT proteins contribute to the levels of glutamate in the brain, the group believes that alteration to the expression of BCAT can contribute to glutamate toxicity thus ultimately causing neuronal cell death leading to the progression of AD.
This work is in collaboration with Dr Katy Chalmers, Dr Patrick Kehoe and Professor Seth Love from the Dementia Research Group, which reflects the expertise over a number of disciplines and allows the enrichment and development of new ideas and concepts to support the success of these projects.
- Clinical research project at The BRACE Centre Dr Liz Coulthard (University of Bristol) In June 2011, a new clinical research initiative started at The BRACE Centre, Frenchay Hospital. Led by Dr Liz Coulthard, it brings together different disciplines and opens up new opportunities for dementia research in the Bristol area.
Several different streams of clinical research are planned focussing on Alzheimer’s disease and other dementias. Each research study involves asking patients and volunteers for their informed consent to take part. At the heart of the research program is a research register where details of willing patients and healthy volunteers are recorded. Using the register, participants are identified as being suitable for a given study. Patients recruited onto the research register and into studies come primarily from the new neurology dementia clinic in the BRACE centre.
Patients are referred to the cognitive neurology and dementia clinic by GPs or other hospital consultants who suspect that they might have some form of dementia. The clinicians then carry out tests to establish what their symptoms mean and, if the cause is dementia, try to establish which form of dementia is involved. Patients attending the clinic are asked if they would like to be entered onto the research register. Much of the research is based in The BRACE Centre ensuring that patients can take part in research in a familiar environment and research and clinical care are closely allied.
Planned research projects will look both at the underlying problems experienced by people who have dementia and also how therapy can be targeted to individual patients. Initial studies are investigating how memory can be affected in dementia. There are several different types of memory including very short term or working memory and longer term memory. We are using computerised cognitive tasks to study the way in which patients retain memory over time and how this could be improved using medication.
Further studies will be based on the preclinical, laboratory-based work of the Dementia Research Group, run by Professor Seth Love and Dr Patrick Kehoe. Their work has demonstrated that blood vessels are affected early in the course of Alzheimer’s disease. Dr Kehoe and Dr Coulthard plan to study the possible beneficial effects of agents that can protect blood vessels and are already used safely to treat high blood pressure. In addition there is the opportunity to help with the early stages of stem research already underway in Bristol and Bath.
In order to measure the effectiveness of treatments, the team is going to perform repeated psychology tests, as well as detailed brain imaging. Repeated volumetric MR imaging of the brain can tell us how much the brain shrinks over time and any benefit of the of the trial drugs on brain volume can be measured. Dr Coulthard is building strong links with the Clinical Research and Imaging Centre (CRIC) in the University of Bristol and the medical physics departments of North Bristol Trust and University Hospital, Bristol, in order to develop high quality image analysis both for clinical and research work.
Netasha Shaikh is an MRC-funded PhD student, supervised by Dr Coulthard and Dr Jack Mellor. She is investigating the possibility that pharmaceutical agents could be used to boost memory consolidation in patients with Alzheimer's disease. She is developing cognitive and EEG measures of memory consolidation to use in a pharmaceutical study funded by BRACE.
BRACE is also funding a dementia neuroimaging project with Professor Risto Kauppinen and Dr Coulthard. This project is a collaboration between Frenchay Neurosciences and CRICBristol.
- The normal function of alpha-synuclein and links to Alzheimer’s disease Prof David Brown (University of Bath)
Research in the group of Professor David Brown at Bath University focuses on proteins associated with neurodegenerative diseases and dementias. In particular the group researches the normal and disease related biology of a protein termed alpha-synuclein that has been linked to Parkinson’s disease. One of the important goals of modern research into brain diseases is to determine why certain proteins change their behaviour and cause disease. This requires that the normal function of these proteins be determined. Recently, David Brown’s group discovered the possibly normal function of alpha-synuclein. The function is related to a trace element in the brain, iron. Alpha-synuclein’s role appears to be to maintain iron in a form that it can be utilised by cells for their normal activity. BRACE co-supports a project aimed at understanding the relevance of this finding to Parkinson’s disease, which commonly involves a form of dementia.
The research group has also begun a new project on the relationship between alpha-synuclein and the amyloid precursor protein (APP). This latter protein is associated with Alzheimer’s disease as it is the protein that generates beta-amyloid, considered the most likely cause of the disease. Alpha-synuclein was originally identified in plaques in the brains of Alzheimer’s diseases as the “non-amyloid component”. However, it was recently suggest that APP also has a role in regards the trace element,iron. Indeed APP and alpha-synuclein have opposing activity in regarding iron. This is highly suggestive of a link between them in handling iron in the cell. A BRACE funded studentship is currently aiding in this investigation.
- Dietary flavonoids and dementia: hype or hope? Dr Rob Williams (University of Bath) and his group are trying to determine whether specific components of the human diet might confer beneficial effects to the brain in Alzheimer’s Disease. His major interest is in a large group of natural substances called Flavonoids which are found in numerous plants and consequently are abundant in foods and drinks derived from plants. The consumption of flavonoid-rich vegetables, fruit juices, green tea and even red wine has been claimed to reduce the risk of developing dementia and to slow age-related memory decline but the rigorous scientific data needed to support their use is lacking.
BRACE is funding work in Rob Williams’ laboratory to develop new sophisticated approaches for testing the effectiveness of dietary flavonoids in cellular models of Alzheimer’s Disease. The objective is to establish if flavonoids work in this system and if so to then determine which of the 4,000 or so different individual flavonoids are most likely to work in dementia. This research represents the crucial first step towards validation of the use of purified flavonoids as therapeutic supplements, will help substantiate health claims for foods rich in flavonoids and hopefully will pave the way for future carefully controlled clinical trials in individuals affected by dementia.
Over time it is hoped that a portfolio of studies will be developed, each designed to improve understanding and treatment of dementia.
- Identifying the causes for increased falls in dementia – a pilot study in healthy older and younger volunteers Dr Ute Leonards and group (University of Bristol).
Walking and balance difficulties with higher risk of falls are common in older adults referred to memory disorder clinics and could be a symptom of a developing dementia. Older adults diagnosed with mild cognitive impairment (MCI) or dementia, irrespective of the type of dementia, show an increased risk of falls leading to serious injuries such as a broken hip. Research into the relationship between the thinking difficulties caused by the dementia and physical changes of walking and balance suggest that walking and balance skills are controlled partly by the thinking skills affected by dementia. However this relationship may vary in different kinds of dementia. Moreover, understanding this relationship in people who have memory problems either in isolation or together with other areas of brain dysfunction (some of which are not measured as part of normal clinical practice) could potentially help to determine for whom such deficits may represent an increased risk of falling (so that preventative measures can be put in place) and also potentially help to identify those for whom such changes represent the early stages of dementia.
In a pilot study with healthy younger and older volunteers, the group aims to isolate the different causes that might increase the risk of falls in older participants. Such knowledge is a prerequisite to identify individuals with MCI in the prodromal stages of dementia as well as to successfully develop interventions that may decrease some of the risk factors for increased falls in patients. Together with Dr John Fennell, Dr Leonards and group are investigating the interplay between walking, visual attention and perception, and link these to general physical function, memory and thinking skills. Using a specially equipped vision and movement laboratory funded by the Wellcome Trust allows them to tease apart the key skills (visual input, attention, thinking skills, physical factors, visual information processing) involved in safe walking. For example, the group explored how accurately people can step onto chosen locations and plan in advance where to step next; both are crucial factors needed to safely traverse more demanding terrains such as walking in autumn over pavements covered in wet slippery leaves. Further, they investigated the impact of floor patterns on walking trajectories and stability. To their surprise, they found that if the direction of floor patterns did not correspond to the direction of walking, the patterns would nudge participants away from their intended trajectory, directly impacting on balance. Such studies provide crucial information on what factors impact on stable walking and what are normal walking-related changes associated with ageing. They will serve in future studies as baseline measure against which to compare people developing dementia, in particular Alzheimer’s disease, and those with MCI.
‘Disease in a Dish’ model for FTD - Dr Vasanta Subramanian and group (University of Bath) Fronto-temporal dementia (FTD) is a commonly occurring dementia in under 65s, accounting for 15–20% of all cases. In FTD, there is progressive neurodegeneration in the frontal and temporal lobes and other brain regions, resulting in behavioral changes, loss of memory and motor neuron deficits. The molecular, cellular, and genetic bases of FTD are only just beginning to be understood. In addition to tau, mutations in other causative genes have been identified recently. Among these are (1) the 43 kD TAR DNA-binding protein (TDP-43), (2) angiogenin and (3) the more recently identified C9orf72 protein. Our ability to study the mechanism of action of the causative factors of Frontotemporal dementia (FTD) is severely limited due to the lack of a steady supply of human neurons from FTD patients. To circumvent this problem Dr Subramanian and her group at the Department of Biology and Biochemistry, University of Bath will use the powerful new technique of reprogramming FTD patient skin cells to generate induced pluripotent stem (iPS) cells and derive neurons and cortical organoids from the iPS cells by directed differentiation. iPS cells are cells resembling embryonic stem cells which are derived by reprogramming cells obtained from adult tissue such as skin or blood cells. It is a powerful new technology (the Nobel prize in Medicine or Physiology, 2012 went to Prof S Yamanaka and Professor Sir John Gurdon FRS for their pioneering work that led to the development of iPS cell technology). The generation of a reliable cell-based model of FTD would be a significant advance. The team has already generated induced pluripotent stem (iPS) cells from skin cells derived from control human subjects and human subjects with ALS-FTD carrying mutations in angiogenin and are able to induce neuronal differentiation from the iPS cells . Neurons and cortical organoids derived from these iPS cells will be used to unravel the molecular and cellular mechanisms underlying FTD and its development. The model can also be used for the development of sensitive assays for screening and testing of therapeutic agents.
- Assessing the contribution of amyloid beta (Aβ) and alpha-synuclein (α-synuclein) to Lewy body-type dementia PhD student, Marta Swirski (University of Bristol) is working with Professor Seth Love and Dr Scott Miners in the Dementia Research Group, and also collaborating with colleagues at UCL and King’s College. Marta’s research concerns the relationship between Aβ and α-synuclein in Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). α-synuclein is present in all nerve cells but becomes abnormally aggregated and forms Lewy bodies in PD, PDD and DLB. What causes the abnormal aggregation of α-synuclein to form Lewy bodies is unclear but research has indicated that a critical step in this process is the modification of α-synuclein by the addition of phosphate at the 129th amino acid along this protein (i.e. phosphorylation of α-synuclein at serine 129). Recent studies suggest that the number of Lewy bodies in the cerebral cortex in PDD and DLB is increased in patients who also have increased numbers of Aβ plaques in the cortex, and Aβ has been shown to induce the addition of phosphate to several constituents of the cell. Marta is investigating whether Aβ also causes the phosphorylation of α-synuclein at serine 129 and, if so, whether this accelerates the progression of PD and promotes the development of dementia. Her research should clarify the nature of the interaction between PD and Alzheimer’s disease and aid in our understanding of the reasons why some people with PD develop dementia.
Modelling Alzheimer’s disease in a culture dish Dr Maeve Caldwell/Prof Seth Love groups University of Bristol. It is well established that the human apolipoprotein E (APOE) gene is a strong genetic risk factor for Alzheimer’s, specifically late onset. The human APOE gene encodes one of 3 isoforms APOE2, APOE3 or APOE4. Specifically individuals carrying APOE4 have an increased risk of developing Alzheimer’s, up to 14 times greater than individuals carrying APOE3 or APOE2. Indeed over 65% of Alzheimer’s patients carry a copy of APOE4. The ability to study the effects of APOE specifically in the human has been limited due to a lack of a true human neuronal model. However, Dr Caldwells group are utilising the technology developed by Nobel prize winner, Shinya Yamanaka to reprogram skin cells from Alzheimer’s patients into induced pluripotent stem (iPS) cells. These iPS cells will carry different APOE genotypes. Once these skin cells are reprogrammed into iPS they can then be converted into basal forebrain cholinergic neurons (bfCN) using methodology developed by Dr Lucy Crompton in the Caldwell lab (Crompton et al., 2013, Stem Cell Res).
Legend for figure: Skin cells collected from Alzheimer’s patients are reprogrammed into a stem cell state, referred to as iPS cells. This is confirmed by expression of the pluripotent stem cell associated proteins TRA-1-60 (green) and SSEA4 (red). We have developed a method of generating basal forebrain cholinergic neurons from these patient derived iPS cells, as shown here labelled with antibodies against with the neuronal marker TUJ1 (red) and Acetylcholinesterase (ChAT shown in green). We will use these neurons to model aspects of Alzheimer’s disease that result in the degeneration of these neurons.
These neurons are involved in memory formation, therefore their dysfunction and degeneration is key to the cognitive decline that typifies Alzheimer’s disease. We will compare bfCNs carrying different APOE genotypes and determine if and why APOE4 positive neurons are more susceptible to ageing in a culture dish, for example developing characteristics of Alzheimer’s disease, and if they are more vulnerable to toxic substances found in the Alzheimer’s disease brain, specifically β-Amyloid. In addition this model will be used to test putative neuroprotective compounds.
Exploring the role of epigenetic changes in Alzheimer’s disease (University of Exeter) Adam Smith is working with Dr Katie Lunnon and Professor Jonathan Mill in the Complex Disease Epigenetics group, exploring the implications of epigenetic changes in a gene called ANK1 in Alzheimer’s disease. The group routinely explore the levels of chemical tags, so-called epigenetic modifications which act to regulate the expression of genes, in a range of diseases.
Recently the group, based at the University of Exeter Medical School, reported evidence for significant epigenetic changes in a gene called ANK1 in Alzheimer’s disease, particularly in regions of the brain that are affected early in the disease. Interestingly, no difference was seen in this gene in areas of the brain largely unaffected by Alzheimer’s disease, or in blood samples collected from the same patients during life. Adam’s PhD studentship, funded by BRACE, is exploring the implications of epigenetic changes in the ANK1 gene, and how this could lead to disease.
Adam’s project will refine the exact extent and location of the epigenetic changes in the ANK1 gene in Alzheimer’s disease, relating this information to both levels of expression of the gene and characteristic measures of disease stage from autopsy examination. He is also investigating other epigenetic modifications that could affect the expression of the gene. One of the most exciting aspects of identifying disease-associated epigenetic changes is that they are potentially reversible and so could represent new drug targets. Adam will also use exciting new epigenetic editing techniques to try to reverse the epigenetic changes in cell model experiments.