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Investigating the role of the regulatory renin-angiotensin system in protecting against synaptic dysfunction in Alzheimer’s disease


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Rationale
Mid-life hypertension is a modifiable risk factor for Alzheimer’s disease (AD) and blood pressure lowering drugs, especially those that target the brain renin-angiotensin system (RAS), lowers the incidence of AD, and reduces the conversion of MCI and slows the progression of AD.

The RAS functions independently within the brain and exerts actions beyond simply blood pressure control. Classical disease-associated RAS pathways (cRAS) are overactivated and associated with disease pathology and cognitive decline in AD (1). Classical RAS (cRAS) activation is regulated by downstream RAS pathways (that prevent cRAS activation) that are defective in AD (2). rRAS pathways do not only improve cerebral blood flow but reduce inflammation and oxidative stress and reverse neurological deficits. Regulatory RAS pathways are also abundantly expressed in the hippocampus and are involved in modulating LTP/LTD and regulating synaptic function that underpins learning and memory (3). We have recently shown that rRAS activation reverses cognitive decline and reduces Aβ and neuroinflammation in an established mouse model of AD (4). The rRAS axis is presenting itself as an ideal candidate to explore as a future route to therapy in AD as it has the potential to influence multiple disease-associated pathways such as Aβ production, tau phosphorylation and brain inflammation, as well as promoting brain plasticity and supporting learning and memory.

Methods
This work will build upon an established collaboration with colleagues at Cardiff (Good) and Bristol (Miners, Whitcomb, Kehoe). It will bring together translationally focused and complementary research in rodents and human brain tissue and will provide further insight into the role of rRAS in relation to disease pathology and synaptic function in AD. The PhD student will be trained in a range of techniques including electrophysiology of nerve cells and hippocampal slices to detailed anatomical dissection of human brain tissue to which they will apply a range of pathological and biochemical techniques. The PhD student will benefit from a highly enriched ‘dementia’ environment at Bristol where Neuroscience is a key research strategy within the University. They will also benefit from a large range of professional and personal development courses provided by the Doctoral college.

This is a self-funded PhD studentship available to all potential UK and oversees students.

References

1. Miners JS, Ashby E, Van Helmond Z, Chalmers KA, Palmer LE, Love S, et al. Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol. 2008;34(2):181-93.

2. Kehoe PG, Wong S, Al Mulhim N, Palmer LE, Miners JS. 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.

3. Hellner K, Walther T, Schubert M, Albrecht D. Angiotensin-(1-7) enhances LTP in the hippocampus through the G-protein-coupled receptor Mas. Mol Cell Neurosci. 2005;29(3):427-35.

4. Evans CE, Miners JS, Piva G, Willis CL, Heard DM, Kidd EJ, 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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