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Amyloid-β-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation

Tai, L. M.; Holloway, K. A.; Male, D. K.; Loughlin, A. J. and Romero, I. A (2010). Amyloid-β-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation. Journal of Cellular and Molecular Medicine, 14(5) pp. 1101–1112.

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DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1111/j.1582-4934.2009.00717.x
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Abstract

Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer's disease (AD). A leaky blood-brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid beta (A?) peptides of 1-40 and 1-42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of A? 1-40, the A? variant found at the highest concentration in human plasma, on the permeability of an immortalised human BEC line, hCMEC/D3. A? 1-40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kDa FITC-dextran when compared to cells incubated with the scrambled A? 1-40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whilst claudin-5 and ZO-1 were unaffected. JNK and p38MAPK inhibition prevented both A? 1-40-mediated down-regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD.

Item Type: Journal Article
ISSN: 1582-1838
Keywords: Alzheimer's disease; Amyloid beta; Blood-brain barrier; Brain; endothelial cells; Occludin; JNK; p38MAPK;
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Innovation, Knowledge & Development research centre (IKD)
Biomedical Research Network (BRN)
Item ID: 12908
Depositing User: Astrid Peterkin
Date Deposited: 14 Apr 2009 13:41
Last Modified: 14 Mar 2014 14:12
URI: http://oro.open.ac.uk/id/eprint/12908
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