About the Project
In the last decade the involvement of the brain Renin Angiotensin System (RAS) in neurodegenerative disease, particularly Alzheimer’s disease (AD) has become a prominent area of research because it may help explain links between the widely known associations between hypertension (and possibly other risk factors) and the development of AD. Some of this, including our own research has already led to the emergence of new clinical trials. At the heart of RAS involvement in AD is the mechanisms and implications of significant imbalances between classical ‘pressor’ and counter-regulatory protective axes of the brain RAS. This provided many opportunities to undertake research to begin to answer several outstanding questions regarding our understanding of the impact of these imbalances on brain function and signalling in general, the potential effect of these in normal ageing, and in turn of the several potential therapeutic options that may exist for age-related cognitive decline and more severe forms of neurodegenerative diseases such as Alzheimer’s disease and related dementias.
Aims & Objectives
We have the knowledge and expertise to train a student to design and execute studies to investigate the extent and impact of RAS imbalance in relation to Alzheimer’s disease and related dementias or or age-related cognitive impairment. Our studies are always directed towards long term translational aims that will benefit patients in the future and the research we undertake has the potential to inform the identification of new mechanisms and/or treatments that would form the basis of tackling the complex multifaceted cognitive and neuropathological aspects of Alzheimer’s disease whilst also continuing to inform the emerging but still incomplete story of the role of the RAS in the brain itself and its normal role in cognitive processes, memory and the neurobiology of the brain.
The following are examples (but not a limited list) of specific hypotheses that we wish to test:
1. To what extent does RAS imbalance occur in Alzheimer’s disease and related dementias
2. To what extent do receptors of the RAS contribute to cognitive decline, Alzheimer’s disease and related dementias
3. How does RAS imbalance associate with imbalance in other pathological processes (e.g. inflammation, oxidative stress, metabolism, neuronal or cerebrovascular dysfunction) in Alzheimer’s disease and related dementias.
There are multiple potential projects available in this topic area and where following consultation we would design a suite of methodological approaches to investigate the agreed research questions. Ordinarily most studies commence with foundation experiments (using molecular genetic, biochemical, immunohistochemical and/or histological approaches) in carefully selected post-mortem brain tissue from diseased and non-diseased persons. These are then usually extended to include complementary studies designed and executed in other laboratory experimental systems (in vitro or cell-culture based), ex vivo (in disease models or more human tissue sources) or in vivo in small pre-clinical trials (time and resources permitting). Projects are intentionally not prescriptive at this stage as we seek to give PhD students the opportunity to develop and design projects with us from the outset as parts of their initial training and input into their projects.
Kehoe PG et al. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-beta and tau pathology. Alzheimers Res Ther. 2016;8(1):50.
Evans CE et al. ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease. Acta Neuropathol. 2020;139(3):485-502.
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