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

• Published in: Journal of cellular and molecular medicine Vol. 14; no. 5; pp. 1101 - 1112
• Main Authors: Tai, L. M., Holloway, K. A., Male, D. K., Loughlin, A. J., Romero, I. A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2010; John Wiley & Sons, Inc
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - pharmacology; amyloid β; Animal models; Antibodies; Blood vessels; Blood-brain barrier; Brain - cytology; brain endothelial cells; Cell activation; Cell culture; Cell Membrane Permeability - drug effects; Cell permeability; Cell Survival - drug effects; Collagen; Dextran; Down-regulation; Down-Regulation - drug effects; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Enzyme Activation - drug effects; Humans; Investigations; JNK; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; MAP kinase; MAP Kinase Signaling System - drug effects; Membrane permeability; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mitogen-Activated Protein Kinases - metabolism; Morphology; mRNA; Neurodegenerative diseases; Occludin; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38MAPK; Peptides; Peptides - pharmacology; Permeability; Protein Kinase Inhibitors - pharmacology; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Therapeutic targets; Tight Junctions - drug effects; Tight Junctions - metabolism; Zonula occludens-1 protein; β-Amyloid; United Kingdom > UK; United States > US; Germany
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2009.00717.x

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 β (Aβ) 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 Aβ 1–40, the Aβ variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Aβ 1–40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC‐dextran when compared with cells incubated with the scrambled Aβ 1–40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin‐5 and ZO‐1 were unaffected. JNK and p38MAPK inhibition prevented both Aβ 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.