Most research at this academic centre is undertaken within the Bristol Dementia Research Group - part of the Department of Care of the Elderly.

This encompasses clinicians, psychologists and scientists working together in our basic neuroscience laboratories, and the Dementia Clinical Research Group. The latter also runs our memory disorders clinic. It isn’t possible to individually list here, all those contributing to the research programme, nor describe all the projects underway, but those mentioned below provide an indication of our interests.

Laboratory based research
We have tissue from almost 700 people in our Brain Bank, and DNA from a further 1000+ individuals with dementia-related illnesses and from a small number of older non-demented people.

During the past year, research has focused on the interrelationships between the brain’s extracellular matrix, cerebral amyloid angiopathy (CAA), which is amyloid that is deposited in blood vessel walls, genetic risk factors for Alzheimer’s Disease (AD) and related disease processes, and the possible influence of those genetic risk factors on normal development and ageing.

Amyloid production and clearance
We are investigating the caveolin system, a family of proteins that are abundant within the brain, particularly in the cerebrovascular endothelium, and in particular Caveolin-1 (CAV-1), which facilitates the normal-secretase mediated cleavage of amyloid precursor protein (APP). This in turn reduces the production of amyloid in the AD brain via the pathological secretase pathways. We have found a loss of CAV-1 from some blood vessels with CAA. This loss is not simply due to endothelial degeneration, which raises the possibility that it may contribute to the development, or cause exacerbation, of CAA.

Research by our molecular neurobiology group has shown that the level of one of the enzymes responsible for producing amyloid from APP in the neuritic plaques and brain parenchyma is nearly doubled in Alzheimer’s disease. Also that a-secretase, the enzyme responsible for normal APP cleavage, is reduced, and that there is an interaction between this and the apolipoprotein E genotype. This has implications for developing treatments.

Genetic risk factors for AD and related disease processes
A substantial part of the work of the group has been aimed at identifying genetic risk factors for AD and related disease processes such as CAA, and at evaluating the possible biological relevance of putative genetic risk factors that have been reported by others and ourselves.

We have also been investigating the TNF-a (tumour necrosis factor-a)/TNF-receptor signalling pathways in AD and their receptor associated protein, TRAF-2. These pathways involve complex interactions leading to the activation of pro-apoptotic or anti-apoptotic signalling cascades.

Our combined approach involving immunohistochemistry, western blotting and direct sequencing of parts of the TRAF-2 gene has suggested that the TNF-a pathway may be involved in the pathogenesis and/or consequences of neurofibrillary tangle formation. This in turn has therapeutic potential.

Extracellular matrix
The perineuronal net (PN) is a specialised region of extracellular matrix (ECM) that surrounds neuronal cell bodies and dendrites. It is thought to be involved in regulating the microenvironment around neurons, in buffering of ions and maintenance of synapses.
We have found that there is a highly significant loss of PNs in the frontal cortex in AD, and are currently investigating the relationship of this to other pathological features of AD, the activity of matrix metalloproteinases and their inhibitors which play a part in PN formation, and to genetic risk factors for AD.

Synaptic density
APOE genotype influences not only risk and age of onset of AD, but also the development of several other neurodegenerative diseases, and in addition the outcome after acute brain trauma. We decided to investigate why it seemed to affect the brain at a more general level, rather than just being a risk factor for AD.

Measuring pre- and post-synaptic markers and linking the levels to APOE genotype in normal brains, revealed that the different APOE genotypes are associated with different levels of synaptic markers, and hence possibly synapses, i.e. reflecting the richness of the neuronal network and its interconnections. This may affect the capacity of individuals to respond to diverse neurological insults and is likely to influence susceptibility to a range of acutely damaging, and chronic degenerative, disease processes within the CNS, not just AD.

Nerve Growth Factor
Nerve growth factor (NGF) is one of a number of growth factors involved in brain plasticity and has specific trophic activity in cholinergic cells, for whose maintenance and survival it is important. It acts by binding on to and activating TrkA, a ‘receptor’ on the neuronal surface. We are looking for small molecules that may mimic NGF by binding to TrkA, thus keeping alive the cholinergic cells that die in AD. We are exploring this using computer modelling to examine the 3D structure of the TrkA receptor and ‘docking’ in millions of compounds to search for the best binders.

Bristol Clinical Dementia Research Group
Clinical research in Bristol concentrates on improving the diagnosis of dementia and its subtypes, and developing and evaluating therapeutic strategies. We also have a rapidly expanding group researching falls in people with dementia.
Of particular interest to us is the emerging evidence that visual attention deficits form a significant factor in both the functional and behavioural aspects of AD. Research in this context includes longitudinal studies to determine whether this can help in identifying the very earliest, i.e. preclinical, stages of AD.
We are exploring the use of transcranial Doppler ultrasonography, measuring cerebral blood flow, as a potential aid to help discriminate those subjects with mild cognitive impairment but who are not demented, who go on to develop a dementia, and which patients with a dementia are most likely to respond to the new treatments for AD.
During the last 15 years the clinical research group have played an important role in evaluating the currently available treatments for AD and other dementias, e.g. cholinesterase inhibitors (we were the first to evaluate galantamine), and memantine. We are also leading a phase II study, on both sides of the Atlantic, of a compound that we believe has “anti-amyloid” properties.
Research is not possible in this day and age without significant financial support, and we have been fortunate over the years in receiving grants from the usual sources, e.g. MRC and Medical Research Charities.

Prof Gordon Wilcock
Dept of Care for the Elderly
University of Bristol