Tai, L. M.; Holloway, K. A.; Male, D. K.; Loughlin, A. J. and Romero, I. A
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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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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|
|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)
|Depositing User:||Astrid Peterkin|
|Date Deposited:||14 Apr 2009 13:41|
|Last Modified:||07 Mar 2014 13:39|
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