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Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine.
- Source :
-
European journal of biochemistry [Eur J Biochem] 2002 Jun; Vol. 269 (12), pp. 3014-22. - Publication Year :
- 2002
-
Abstract
- Tauhe main component of cerebral amyloid angiopathy (CAA) in Alzheimer's disease is the amyloid-beta protein (Abeta), a 4-kDa polypeptide derived from the beta-amyloid protein precursor (APP). The accumulation of Abeta in the basement membrane has been implicated in the degeneration of adjacent vascular smooth muscle cells (VSMC). However, the mechanism of Abeta toxicity is still unclear. In this study, we examined the effect of substrate-bound Abeta 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 Abeta 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 Abeta 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 Abeta significantly reduced cell adhesion compared to cells grown on plastic alone, indicating that cell-substrate adhesion may be important in maintaining cell viability. Abeta 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 disease, increased Abeta-induced toxicity and caspase-3 activation in a dose-dependent manner. These studies suggest that Abeta may activate apoptotic pathways to cause loss of VSMC in CAA by inhibiting cell-substrate interactions. Our studies also suggest that homocysteine, a known risk factor for other cardiovascular diseases, could also be a risk factor for hemorrhagic stroke associated with CAA.
- Subjects :
- Amyloid beta-Peptides agonists
Amyloid beta-Peptides metabolism
Amyloid beta-Peptides pharmacology
Animals
Apoptosis physiology
Caspase 3
Caspases drug effects
Cell Adhesion physiology
Cells, Cultured
Hydrogen Peroxide metabolism
Membrane Glycoproteins
Muscle, Smooth, Vascular cytology
Peptide Fragments agonists
Peptide Fragments pharmacology
Rats
Rats, Inbred WKY
Rats, Sprague-Dawley
Amyloid beta-Peptides toxicity
Caspases metabolism
Homocysteine pharmacology
Hydrogen Peroxide toxicity
Muscle, Smooth, Vascular drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2956
- Volume :
- 269
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- European journal of biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12071966
- Full Text :
- https://doi.org/10.1046/j.1432-1033.2002.02976.x