Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells.
Alzheimer's disease is characterised by neuronal loss, numerous intraneuronal deposits of neurofibrillary tangles, senile plaques, and cerebrovascular amyloid deposits. The major component of senile plaques and cerebrovascular deposits is the 39-43 amino acid beta-amyloid peptide (Abeta). The effects of Abeta on cerebral endothelium and thus the blood-brain barrier remain unclear. Utilising endothelial cells isolated from rat cerebral cortex microvessels, we have examined effects of Abeta peptides on tight junction protein behaviour. The transmembrane tight junction proteins occludin, claudin-1 and claudin-5, as well as the cytoplasmic accessory proteins ZO-1 and ZO-2 displayed a continuous distribution at cell boundaries. Endothelial cells exposed to Abeta1-42 (20 microM) for 3 days showed a disrupted plasma membrane pattern of claudin-5 and ZO-2 with relocation to the cytoplasm. These effects were not seen with Abeta25-35 or Abeta1-40[Gln22] (Dutch type). Abeta1-42 treatment altered also protein expression: occludin was lower at 1st day, claudin-1 increased at all times, and ZO-2 increased after 1 day and then decreased. These data suggest that Abeta1-42 effects on tight junction protein complexes may alter blood-brain barrier integrity and contribute to the neuropathological sequelae of Alzheimer's disease.
Marco
Sonia
S
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, CM19 5AW Harlow, Essex, United Kingdom.
Skaper
Stephen D
SD
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000033:anatomy & histology; D062445:Claudin-1; D057167:Claudins; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology*; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism*; D062793:Occludin; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
D016229:Amyloid beta-Peptides; D062445:Claudin-1; D057167:Claudins; C568114:Cldn1 protein, rat; C491874:Cldn2 protein, rat; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)