The emerging role of RAS in Alzheimer’s disease and dementia

The Dementia Research Group at Bristol is the most widely published group and thus to the forefront of the emerging involvement of the renin angiotensin system (RAS) in the pathology of Alzheimer’s disease (AD). Over the last decade the work by members of the group has provided the largest body of data investigating the role of the pathway in post mortem human brain tissue to provide the requisite translational bridge between pre-clinical in vitro and in vivo modelling of the role of RAS in Alzheimer’s disease with observational studies in populations. Changes to the classical RAS pathway and more recently a counter-regulatory pathway are consistently associated with the neuropathology of Alzheimer’s disease. The net effect of these changes now strongly supports the involvement of angiotensin II signalling and its multifunctional properties in numerous aspects of Alzheimer’s disease pathology and reinforces its candidacy as a viable therapeutic target for Alzheimer’s disease. Successful interference with angiotensin II signalling is likely to have a positive effect on the likely roles of angiotensin II in inflammatory, neurotoxic and anti-cholinergic mechanisms in Alzheimer’s disease as well as influencing blood flow around the brain with potential involvement in other important signalling cell signalling mechanisms.

More recently a number of converging lines of evidence from other neurological conditions (e.g. Vascular Dementia, Vascular Cognitive Impairment, Parkinson’s disease and Multiple Sclerosis) all seem to have elements of their pathology or development that may either be related to changes in the RAS or where modulation of the RAS might influence the pathological evolution of the disease. Such changes might have a bearing on patient prognosis and clinical outcomes, that similar to Alzheimer’s disease may provide scope for future interventions through the use of the existing array of RAS-targeting drugs, the majority of which have been designed to treat hypertension, however where, as is thought to be the case in Alzheimer’s disease, may have the scope to elicit additional effects independent of blood pressuring lower functions. The Bristol Dementia Group is one of the largest research groups in Clinical Neuroscience in the Faculty of Health Sciences and is based at the state-of- the-art Learning and Research Building at the new Southmead Hospital, Bristol. The group is also a member of the Institute of Clinical Neurosciences that brings together specialists in Translational (pre-clinical and clinical) Clinical Neuroscience Research that have interests in (Multiple Sclerosis, Parkinson’s disease and Various forms of Cognitive Impairment associated with Cerebrovascular disease).

We invite outline proposals (up to 2 pages of A4 (font size 12 max) with headings Research Question, Background, Methods & Approaches to answer the Research Question, and a brief comment on likely clinical impact) from prospective self- or externally funded PhD students of a potential course of work to further explore aspects of RAS involvement in Alzheimer’s disease, other forms of dementia or some of the other Neurological conditions mentioned. Such work would have the scope to integrate with research undertaken by the Dementia Research Group to-date either independently or through collaboration in the Institute of Clinical Neurosciences. In the email correspondence associated with the outline please also give details of what funding is available to support the project.

The Bristol Dementia Group also has a wide and extensive network of collaborators that provides broad scope in which to frame a focused project and we welcome proposals that are novel and seek to address existing gaps in existing knowledge or to extend/create new lines of enquiry existing knowledge. This will provide a fantastic opportunity for motivated students to frame a PhD to their own hypothesis driven work, and link with one of a number leading International Clinical Neuroscience Groups in the UK.