tailieunhanh - Báo cáo Y học: Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine

The main component of cerebral amyloid angiopathy (CAA) in Alzheimer’s disease is the amyloid-b protein (Ab), a 4-kDa polypeptide derived from the b-amyloid protein precursor (APP). The accumulation of Ab in the basement membrane has been implicated in the degeneration of adjacent vascular smooth muscle cells (VSMC). However, the mechanism of Ab toxicity is still unclear. In this study, we examined the effect of substrate-bound Ab on VSMC in culture. The use of substrate-bound proteins in cell culture mimics presentation of the proteins to cells as if bound to the basement membrane. Substrate-bound Ab peptides were found to be toxic. | Eur. J. Biochem. 269 3014-3022 2002 FEBS 2002 doi Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine Su San Mok1 2 Bradlev J. Turner1 2 Konrad Bevreuther3 Colin L Masters1 2 Colin J. Barrow4 B B B and David Hb Small1 2 1Department of Pathology The University of Melbourne Parkville Victoria Australia 2The Mental Health Research Institute of Victoria Royal Park Hospital Parkville Victoria Australia The University of Heidelberg Heidelberg Germany 4The School of Chemistry The University of Melbourne Parkville Victoria Australia The main component of cerebral amyloid angiopathy CAA in Alzheimer s disease is the amyloid-b protein Ab a 4-kDa polypeptide derived from the b-amyloid protein precursor APP . The accumulation of Ab in the basement membrane has been implicated in the degeneration of adjacent vascular smooth muscle cells VSMC . However the mechanism of Ab toxicity is still unclear. In this study we examined the effect of substrate-bound Ab on VSMC in culture. The use of substrate-bound proteins in cell culture mimics presentation of the proteins to cells as if bound to the basement membrane. Substrate-bound Ab peptides were found to be toxic to the cells and to increase the rate of cell death. This toxicity was dependent on the length of time the peptide was allowed to age a process by which Ab is induced to aggregate over several hours to days. Oxidative stress via hydrogen peroxide H2O2 release was not involved in the toxic effect as no decrease in toxicity was observed in the presence of catalase. However substrate-bound Ab significantly reduced cell adhesion compared to cells grown on plastic alone indicating that cell-substrate adhesion may be important in maintaining cell viability. Ab also caused an increase in the number of apoptotic cells. This increase in apoptosis was accompanied by activation of caspase-3. Homocysteine a known risk factor for cerebrovascular