title: The beta-amyloid peptide of Alzheimer's disease decreases adhesion of vascular smooth muscle cells to the basement membrane.
abstract: Cerebral amyloid angiopathy (CAA) is a major feature of Alzheimer's disease pathology. In CAA, degeneration of vascular smooth muscle cells (VSMCs) occurs close to regions of the basement membrane where the amyloid protein (Abeta) builds up. In this study, the possibility that Abeta disrupts adhesive interactions between VSMCs and the basement membrane was examined. VSMCs were cultured on a commercial basement membrane substrate (Matrigel). The presence of Abeta in the Matrigel decreased cell-substrate adhesion and cell viability. Full-length oligomeric Abeta was required for the effect, as N- and C-terminally truncated peptide analogues did not inhibit adhesion. Abeta that was fluorescently labelled at the N-terminus (fluo-Abeta) bound to Matrigel as well as to the basement membrane heparan sulfate proteoglycan (HSPG) perlecan and laminin. Adhesion of VSMCs to perlecan or laminin was decreased by Abeta. As perlecan influences VSMC viability through the extracellular signal-regulated kinase (ERK)1/2 signalling pathway, the effect of Abeta1-40 on ERK1/2 phosphorylation was examined. The level of phospho-ERK1/2 was decreased in cells following Abeta treatment. An inhibitor of ERK1/2 phosphorylation enhanced the effect of Abeta on cell adhesion. The studies suggest that Abeta can decrease VSMC viability by disrupting VSMC-extracellular matrix (ECM) adhesion.
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Su San
authors.initials: SS
authors.lastname: Mok
authors.forename: Dusan
authors.initials: D
authors.lastname: Losic
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Barrow
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Lisandra L
authors.initials: LL
authors.lastname: Martin
authors.forename: David H
authors.initials: DH
authors.lastname: Small
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis* / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005822:Genetic Vectors; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D014162:Transfection; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002518:Ceramides; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide