Activities of the Team
Prof. StJohn Crean has an extensive experience in Alzheimer’s disease research, particularly in relation to the role of oral bacteria.
Prof. Colin Davidson has an interest in neurodegeneration and has published in the fields of pre-clinical stroke research and drug abuse where methamphetamine has been shown to be neurotoxic, especially to the dopamine system. He uses fast cyclic voltammetry to measure neurotransmitters in brain tissue and rodent behavioural models to test novel therapeutics.
Dr. Sim K. Singhrao main interest lies in firmly establishing periodontal pathogens being a risk factor for the development of Alzheimer’s disease. The ultimate aim is to suggest a programme of health through scientific evidence by changing lifestyles and preventing hundreds of unnecessary sporadic dementia cases arising every year.
Dr Jane Alder has developed a novel human three-dimensional in vitro blood brain barrier (BBB) model from primary cells with realistic architecture and dynamic flow for the study of BBB dysfunction associated with neurodegenerative pathogenesis.
Dr Anthony Ashton’s group has characterized in depth the fact that synaptic vesicles can undergo both full fusion and kiss-and-run exocytosis and that vesicles can switch between these modes dependent upon the stimulation conditions and the precise pool of vesicles undergoing release. The switch is controlled by calcium levels and protein phosphorylation and we have established that two proteins – dynamin 1 and non-muscle myosin 2 – can regulate the kiss-and-run mode by closing the fusion pore. These results have been presented at several international meetings and is currently being submitted for publication. The relationships between these changes and Alzheimer’s disease (this has been referred to sometimes as type 4 diabetes) are being investigated. Current research on these modes have indicated that cAMP and PKA can also regulate these and the relationship between this and the role of calcium is being sought.
The group have been able to biochemically distinguish between the readily releasable and reserve pool/recycling pool of synaptic vesicles and this will enable the investigation of such pools in various models of disease including various neurodegenerative diseases and autism. Recently, they have investigated the silent pool (also called the reluctant or resting pool) of vesicles. These vesicles don’t normally contribute to release but certain conditions can induce these vesicles to undergo exocytosis. The Ashton group have been investigating the properties of silent pool of vesicles including whether specific calcium channels can regulate their release and whether certain protein kinases regulate their properties. The relationship between this pool and the phosphorylation state of synapsin 1 is being determined. Finally, an exciting project involves studying the role of alpha-synuclein in regulating this pool and the other pools of vesicles and whether this is regulated by phosphorylation of this protein. This is particularly exciting as aberrant phosphorylation of alpha-synuclein has been suggested to play a role in Parkinson’s disease as has aggregation of this protein. This research is important as the normal role of alpha-synuclein has not been fully elucidated.
Dr Vicky Jones is focused on the role of glia in the pathogenesis of neurodegenerative disorders including Alzheimer’s, Parkinson’s and Motor Neurone Disease. Dr Jones’ recent work described the production of induced pluripotent stem cell-derived mature astrocytes from patients with both early- and late-onset Alzheimer’s disease (EOAD and LOAD, respectively) as a model for the study of astrocytic dysfunction in the pre-clinical stages of the disease. Her work provided the first evidence of AD-associated astrocytic atrophy in human cells and in LOAD (having previously only been described in mouse models of EOAD), further implicating astrocyte pathology as an early determinant in Alzheimer’s. Dr Jones’ group is currently concerned with dissecting the molecular mechanisms underlying such atrophy and in uncovering the functional effects such cells have on synaptic function and plasticity (key determinants of learning and memory).
Dr Jones is also undertaking projects investigating the effects of Parkinson’s-associated genetic mutations and of newly-identified Alzheimer’s risk genes in astrocyte morphology and function. She is further working alongside Dr Suresh Chhetri (Consultant Neurologist at the Royal Preston Hospital) on a George Barton Motor Neurone Disease (MND) Trust-funded project to identify circulating biomarkers in MND patient blood which can be used to develop diagnostic and prognostic tools.
Dr Chris Smith’s experience of in vivo microdialysis can be applied to disparate conditions from glioma to Alzheimer’s disease where the neurochemistry of the brain can be monitored in situ in the living organism as the disease progresses. In addition the technique can be used to determine the effect pharmacological agents would have on the release of neurotransmitters. A powerful aspect of in vivo pharmacology is combining microdialysis with behavioural studies to correlate the brain neurochemistry with behaviour, an ambition that is currently being worked towards as viral vectors currently being developed to induce mutations in neuronal signalling mechanisms (Vicky Jones) will ultimately be applied to the freely moving organism.
Dr Donna Daly’s research aims to understand how the sensory nerves innervating the visceral organs such as the bowel and bladder detect normal mechanical and chemical stimuli, and how these signals are altered in neurodegenerative conditions such as ageing. She is also interested in the peripheral mechanisms of pain sensation and how this is also altered with natural ageing or due to disease.
Dr Jamal Nasir has a long standing interest in the genetics of neurodegenerative and neurodevelopmental disorders, including Huntington’s disease (HD). Jamal described the first published knock out mouse model for HD (Nasir et al., Cell. 1993). More recently, he and his team have been exploring the genetics of neurodevelopmental disorders through investigating consanguineous populations and have undertaken functional studies of the relevant genes and their roles in various processes in the cell through external collaborations. Dr Nasir has also been investigated the dopamine signalling pathway at the molecular level and identified novel dopamine receptor interacting proteins (DRIPs). Finally, in collaboration with researchers at UCL, Dr Nasir is undertaking genomics and proteomics studies of stroke and various other conditions, including ALS, schizophrenia and Parkinson’s disease.
Dr Inmaculada Gonzalez: Neurotransmitter receptor insertion and removal to and from synapsis underlie many forms of experience-dependent plasticity including learning and memory. Understanding the processes that controls the surface expression, maintenance and dynamics of neurotransmitter receptors is key to establish the cellular and molecular basis of the excitatory transmission and synaptic plasticity in memory, cognition and normal brain function.
Dr Milos Petrovic and Dr Craig Bertram are engaged in the Parkinson’s disease research (specifically the pathogenetic mechanisms underlying the L-DOPA-induced dyskinesia), as well as the disturbance of glutamatergic signalling in dementia models (e.g frontotemporal dementia, FTD).