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Does the brain renin angiotensin system influence the occurrence of depression in Alzheimer’s disease?


Bristol Medical School

About the Project

Rationale
In the last decade the involvement of imbalance in counterbalancing arms of the brain Renin Angiotensin System (RAS) has been found to be a significant factor in Alzheimer’s disease (AD). Other, functions of the RAS in the brain include evidence of its involvement with various neurotransmitters pathways, including those implicated in the neurobiology of some types of depression, which is the predominant mental health problem globally but also occurs frequently in AD. Moreover, RAS-blocker drugs commonly used in the management of most common forms of hypertension, to reduce angiotensin II-receptor signalling in the ‘classical’ RAS, have been proposed as possible treatments for both AD and possibly in depression.

What is not known is whether the presence or extent of RAS imbalance has any bearing on the presence or absence of depression as a co-morbidity in AD, which might inform whether proposed trials of RAS-blocking drugs in AD may be more likely to be effective in sub-groups of patients that may or may not have a history of or co-occurring depression.

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 have the scope to access post-mortem and potentially other patient-related biosamples from patients who had or had not depression either before or during the course of their Alzheimer’s disease. We design projects that are always directed towards longer term translational outcomes that will benefit patients in the future and where the research that is undertaken has the potential to inform the identification of new mechanisms and/or treatments to be tested in future clinical trials. This project, whilst delving more deeply into the complex relationship between AD and depression will continue to inform the emerging but still incomplete story of the role of the RAS in the brain itself and its normal role in cognition 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 in presence or absence of depression.
2. To what extent does prior history of depression in Alzheimer’s disease influence changes in RAS.
3. To what extent do receptors of the RAS contribute to neuropathological hallmarks in Alzheimer’s disease in the presence or absence of depression.

Methods
There are several projects possible in this topic area and as such we are intentionally not prescriptive at this stage since we seek to give PhD students the opportunity to develop and design their future projects with us from the outset as part of their initial training. In doing so we would design a suite of methodological approaches to investigate the agreed research questions and 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 and in this case selected according to the presence of absence of co-occurring and/or previous history of depression. These are then usually extended to include complementary in vitro, cell-culture based or ex vivo studies (time and resources permitting) to provide further validation experiments to place.

References

Kehoe PG. The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment? J Alzheimers Dis. 2018;62(3):1443-66.

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.

Belujon P, Grace AA. Dopamine System Dysregulation in Major Depressive Disorders. Int J Neuropsychopharmacol. 2017;20(12):1036-46.

Labandeira-Garcia JL, Garrido-Gil P, Rodriguez-Pallares J, Valenzuela R, Borrajo A, Rodriguez-Perez AI. Brain renin-angiotensin system and dopaminergic cell vulnerability. Front Neuroanat. 2014;8:67

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