Research project: The Role of Arterial Pulsations in Perivascular Drainage and its Implications for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common form of dementia and poses a serious health risk all over the world, with 35.6 million cases worldwide in 2010 and an estimated 70 million cases by 2030. The disease is lethal in every case and to date there is no cure as the processes relevant to the onset and progression of the disease have not been fully understood yet.

Amyloid-beta (Aβ) is one of the key players in AD. The protein is produced as a waste product by neuronal cells and its accumulation in the walls of cerebral blood vessels is closely associated with the onset and progression of AD (Weller et al., 2009). The production of Aβ is normal in healthy individuals, however, it is required to be transported from the brain to the lymphatic system of the body. Failure of the transport mechanisms, which are not fully understood, leads to the deposition of Aβ in the basement membranes of cerebral arteries (Weller et al., 2008).
The way Aβ is deposited in the brain of AD patients suggests that perivascular drainage pathways within the basement membranes are the routes for solutes like Aβ alongside intersitial fluid (ISF) (Weller et al. 2009). Our understanding of the mechanisms that drive perivascular drainage of Aβ is still very limited as experimental results suggest that ISF flow within the basement membranes happes in the reverse direction of the blood flow within the arteries.

With this PhD project we seek to shed light onto the motif force that drives perivascular drainage. Heart rate driven pulsations of the arteries are an interesting candidate and a model has been developed to investigate the feasibility of such a reverse pump (Schley et al. 2006). These pulsations would be able to explain why the Aβ drainage process slows down and fails with age as capillaries and arteries stiffen and become less responsive to the pulsations created by the heart beat. However, this model proposes a valve-like mechanism within the basement membrane, which is not explained by the model and therefore the model does not resolve the question of what drives perivascular drainage.
The key challenge in perivascular drainage research is that the basement membranes are very inaccessible for direct medical experiments as they are only about 100-150 nm wide. Therefore it is necessary to take steps towards the development of a model framework, which can be used to investigate the properties of perivascular drainage and how changes in these properties affect the efficiency of the drainage. The basement membrane consisits of extracellular matrix, which is a dense network of several types of proteins. The working hypothesis states that these proteins have certain bending properties, which allow flow in only one direction, that is the reverse direction of the blood flow. During the project we aim to test and develop this hypothesis further. We are aiming to establish the key properties of how arterial pulsations affect perivascular drainage and how these effects fail during age. A deeper understanding of the underlying processes of the Aβ drainage processes is key for the development of efficient treatment and also prevention of AD. Its existence had been established over 100 years ago, but our understanding of it is still extremely limited, which proves the necessity of a multidisciplinary simulation approach to this problem.

References:
R. O. Carare, M. Bernardes-Silva, T. A. Newman, A. M. Page, J. A. R. Nicoll, V. H. Perry and R. O. Weller: Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathology and Applied Neuobiology 34(2):131-144, 2008.
D. Schley, R. Carare-Nnadi, C. P. Please, V. H. Perry and R. O. Weller: Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of Theoretical Biology 238(4):962-974, 2006.
R. O. Weller, M. Subash, S. D. Preston, I. Mazanti and R. O. Carare: Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathology 18(2):253-266, 2008.
R. O. Weller, R. O. Carare and D. Boche: Amyloid: Vascular and Parenchymal. In L. R. Squire, editor, Encyclopedia of Neuroscience , volume 1, pages 355-362, Academic Press, Oxford, 2009