Cycle 3 project 7

Understanding blood-brain barrier alterations underlying capillary amyloid angiopathy: a route to novel diagnostics?


PhD student: Hripsime Snkhchyan, Armenia
Home Institute: Amsterdam Neuroscience; Principle Investigator: Elga de Vries / Annemieke Rozemuller
Host Institutes:
Neuroscience Center Zürich; Principle Investigator: Roger Nitsch
Bordeaux Neurocampus; Principle Investigator: Klaus Petry

Executive Summary

Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer’s disease (AD) and is marked by deposition of amyloid beta (Aβ) in leptomeningeal and cortical brain vasculature. In over 40{4f6e60e6953937a1ab815e93856ab9862da64473b2fafe2c234a4daba9520ef4} of AD cases, Aβ mainly accumulates in cortical capillaries, a phenomenon referred to as capillary CAA (capCAA), a subtype of CAA. Previously, we have shown that a strong neuroinflammatory response occurs specifically around capCAA vessels with dyshoric Aβ deposits (Richard et al., J Neuropathol Exp Neurol. 2010). In our recent study (Carrano et al., Antioxid Redox Signal. 2011), we have shown that Aβ associated with capillaries strongly reduces the expression of tight junction proteins of the blood-brain barrier (BBB). Strikingly, in post-mortem tissue derived from AD patients without capCAA, no changes at the levels of the tight junctions was apparent. These findings indicate a strong impact of capCAA on the pathogenesis of AD. Importantly, proteins at the BBB are known to closely control the clearance of Aβ from the brain parenchyma, thereby preventing Aβ accumulation. Specifically, members of the ATP-binding cassette transporters family (P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and multidrug resistance-associated proteins-1 and -2 (MRP-1, MRP-2)) actively regulate the removal of Aβ from the brain.

Research leading to this proposal:
We have identified, in well-characterized post-mortem material, that capCAA brains show a striking reduction in the expression of the ABC transporters, in particular P-gp, in comparison to controls and AD cases .

U sing our functional in vitro assays for the function of P-gp (Kooij et al., J Autoimmun. 2009), we were able to show that administration of Aβ peptide 1-42 to cultures of human brain endothelial cells significantly reduced the efflux capacity of P-gp. Together, these data indicate that loss of the function of P-gp at the BBB may serve as a selective pathological marker for capCAA.

Originality and innovative aspects of the proposal
Our preliminary data further suggest that in capCAA tissue, P-gp expression is also reduced at capillaries without amyloid deposits; including the temporal lobe, the predilection site for capCAA. We therefore hypothesize that loss of P-gp activity may serve as a marker for the onset of capCAA and that alterations of P-gp at the cerebral capillaries are key to capCAA mediating consequent disease progression. The identification of underlying mechanisms of observed alterations of P-gp at the cerebral microvasculature in capCAA may hold the key for novel intervention strategies to limit Ab accumulation within the brain thus preventing cognitive decline and concomitant neurodegeneration.

Rationale for collaboration
In order to unravel the underlying mechanisms of altered P-gp expression in the course of disease, a multi-disciplinary translational approach is required that synergizes human pathology (Rozemuller) animal-models (Nitsch) and in vitro methods (De Vries). Importantly, basic training in the in vivo imaging of blood-brain barrier function will be obtained in the group of prof.dr. Klaus Petry, INSERM Bordeaux, France. Such collaborative synergies are only feasible through the ENC-Network program.”



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