Blood-brain barrier alterations in multiple sclerosis and capillary cerebral amyloid angiopathy.
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1
VU University Medical Center, Department of Molecular Cell Biology and Immunology, Netherlands
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2
VU University Medical Center, Department of Pathology, Netherlands
Optimal function of the blood-brain barrier is crucial for the homeostasis of the central nervous system (CNS) and protects the brain from unwanted compounds and cells. However, an altered function of the blood-brain barrier is thought to contribute to a number of neurological disorders, such as vascular dementia or multiple sclerosis. To date, not all aspects of barrier function are revealed, which is the topic of this presentation.
A defective function of the BBB has been described for a variety of brain disorders including multiple sclerosis (MS) a chronic inflammatory disease of the CNS characterized by the presence of multiple demyelinated lesions scattered throughout the CNS. Active MS lesions contain high numbers of inflammatory cells, mainly T cells and monocyte-derived macrophages, of which the latter mainly contribute to tissue damage, demyelination and axonal dysfunction. So far, most studies focused on the defects in the integrity of the BBB during MS, including tight junction and basement membrane alterations that lead to cellular influx. Data on the molecular properties of the BBB under neuroinflammatory conditions are scarce. P-gp is a key ABC transporter located at the BBB, which effectively removes a remarkably wide variety of substrates out of the brain, including inflammatory agents. P-gp is known as the gatekeeper of the brain, and effective P-gp function is therefore critical in the maintenance of brain homeostasis.
Notably, we demonstrated that T-cells can induce the impaired endothelial function of P-gp in a ICAM-1 selective manner, in which signalling through NF-kB was of importance (Figure 2)
Another neurological disorder that affects the brain vasculature is cerebral amyloid angiopathy (CAA). CAA is characterized by deposition of amyloid beta in the walls of cerebral and leptomeningeal vessels. Though CAA shows a high prevalence in normal elderly population (50%), almost all cases of Alzheimer disease present with CAA. Cerebrovascular amyloid deposits are seen in leptomeningeal and cortical arteries, and less frequently in veins and capillaries as well as in subcortical vessels. Several groups support the distinction between CAA present in larger vessels and Aβ accumulation in both vessels and capillaries. Here, CAA also present in capillaries is referred to as capillary CAA (capCAA). In some cases, vascular Aβ radiates into the surrounding neuropil, a phenomenon named ‘dyshoric angiopathy’, which literally means dysfunction of the blood-brain barrier (horos: border; dyshoros, malfunctioning of border, barrier).
Leaking of the BBB in CAA and AD has been suggested by the detection of plasma proteins associated with amyloid plaques and within AD brain parenchyma together with increases in microvascular permeability associated with cerebrovascular Abeta deposits. However, to date neuropathological data on the status of the blood-brain barrier are lacking and preliminary findings on that topic will be discussed.
Together, our data strongly suggest that malfunction of the BBB at the level of the tight junctions as well as on the level of the ABC transporters is an important pathological feature of neurological disorders.
References
1. Kooij G, van Horssen J, de Lange EC, Reijerkerk A, van der Pol SM, van Het Hof B, Drexhage J, Vennegoor A, Killestein J, Scheffer G, Oerlemans R, Scheper R, van der Valk P, Dijkstra CD, de Vries HE. T lymphocytes impair P-glycoprotein function during neuroinflammation. J Autoimmun. 2009 Dec 1. [Epub ahead of print].
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Kooij
G,
Carrano
A,
Reijerkerk
A,
Mizee
M,
Van Horssen
J,
Rozemuller
A,
Van Der Valk
P and
E De Vries
H
(2010). Blood-brain barrier alterations in multiple sclerosis and capillary cerebral amyloid angiopathy..
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00017
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Received:
10 Mar 2010;
Published Online:
10 Mar 2010.
*
Correspondence:
Helga E De Vries, VU University Medical Center, Department of Molecular Cell Biology and Immunology, Amsterdam, Netherlands, he.devries@vumc.nl