Dementia is associated with amyloid beta (Aβ) deposition in neuronal tissue, but also along the walls of arteries. Evidence for a major drainage pathway along the walls of arteries is recently emerging 1. More specifically, Aβ is proposed to drain along the basement membranes of arterial smooth muscle cells. Such a transport mechanism appears to be unique to the brain, and could be considered as an alternative to the lymphatic system.
Hypothesis: We propose that vascular pathologies, such as hypertension, reduced blood flow, ischemia and aging lead to remodeling of resistance artery basement membranes and extracellular matrix, such that these impair Aβ-drainage.
Objectives: In this project we will study the role of the resistance artery extracellular matrix in the perivascular transport of Aβ. We will study the impact of vascular pathology and aging on the efficiency of this transport mechanism. The first objective will be to trace the fate of locally injected fluorescently labeled Aβ, by comparing fluorescence intensity around arteries, veins and the parenchyma in the brain. Subsequently, the kinetics of the removal will be compared under a variety of vascular pathological conditions.
Training: The ESR will be trained by the host institute to use a recently developed cranial window. This model consists of surgical removal of part of the skull in rodents, and visualization of the vasculature with a combination of fluorescence and side-stream dark field imaging. The ESR will then be trained to manipulate blood flow and pressure, by ligation of the carotid artery; and use animal models of hypertension and aging. Training on the in vivo measurements will be complemented with analysis of basement membrane components (laminins, collagens, nidogen, proteoglycans, and others) and electron microscopy. As this project depends on expertise regarding the basement membrane in particular of brain vessels, the ESR will spend part of the project in Munster. Associated partner VIS will be involved for the assessment of the hemodynamic interventions (blood flow reduction, ischemia) using ultrasound and near-infrared spectroscopy.
1 Brain Pathol. 2008;18(2):253-66.
Bedussi, B., van Lier, M.G.J.T.B., Bartstra, J.W., de Vos, J., Siebes, M., VanBavel, E., & Bakker, E.N.T.P. (2015). Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system. Fluids and Barriers of the CNS, 12:23.
Bakker, E.N.T.P., Bacskai, B.J., Arbel-Ornath, M., Aldea, R., Bedussi, B., Morris, A.W.J., Weller, R.O., & Carare, R.O. (2015). Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases. Cellular and Molecular Neurobiology, 36, 181-194.
Bedussi, B., van der Wel, N.N., de Vos, J., van Veen, H., Siebes, M., VanBavel, E., & Bakker, E.N. (2016). Paravascular channels, cisterns, and the subarachnoid space in the rat brain: A single compartment with preferential pathways. J. Cereb. Blood Flow Metab., doi: 10.1177/0271678X16655550.
Bedussi, B., Naessens, D.M.P., de Vos, J., Olde Engberink, R., Wilhelmus, M.M.M., Richard, E., ten Hove, M., vanBavel, E., Bakker, E.N.T.P. Enhanced interstitial fluid drainage in the hippocampus of spontaneously hypertensive rats. Submitted.
Ph.D student / post-doc
Prof. van Bavel