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Investigating the timing and causes of vascular dysfunction in Alzheimer’s disease


Bristol Medical School

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

About the Project

Rationale
Cerebrovascular damage accelerates and exacerbates cognitive decline and brain damage in Alzheimer's disease (AD)(1, 2). These processes are major contributors to disease progression from an early stage, causing impairment of neurovascular coupling, reduction in cerebral perfusion, leakage of toxic serum proteins into the brain parenchyma, and impaired clearance of Aβ and other toxic metabolites from the brain. Pericytes, mural cells enriched within brain capillaries, are key regulators of vascular function but degenerate in AD(3). Recent studies indicate that pericyte dysfunction is an early abnormality in the disease process, occurring years before the onset of clinical symptoms(4).

Aims and objectives
This PhD will build upon ongoing studies in the lab to determine the timing and causes of pericyte dysfunction and vascular breakdown in AD.

Methods: The PhD student will employ a range of techniques, to (i) explore the timing of pericyte loss in relation to disease pathology in human post-mortem tissue in AD and in relation to the onset and development of cognitive decline, and onset of disease pathology, in CSF samples from large pre-clinical longitudinal studies; to (ii) investigate the major causes of pericyte dysfunction and degeneration in human brain pericyte cultures and develop cutting-edge models of the BBB and neurovascular unit; and (iii) will investigate the role of pericytes and the BBB in the clearance Aβ from the brain. A better understanding of the timing and causes of pericyte and BBB dysfunction in AD will allow us to identify and test novel targets to prevent vascular dysfunction and disease progression in AD.

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

References

1. Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018;21(10):1318-31.

2. Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-The disregarded partner of Alzheimer's disease. Alzheimers Dement. 2019;15(1):158-67.

3. Miners JS, Schulz I, Love S. Differing associations between Abeta accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer's disease. J Cereb Blood Flow Metab. 2018;38(1):103-15.

4. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270-6.

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