The effect of overexpression of amyloid precursor protein in different cell types of vascular tissue

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Vascular damage as a result of amyloid precursor protein (APP) and amyloid protein (Aβ) accumulation is observed in brain vasculature of patients with Alzheimer's disease and cerebral amyloid angiopathy (CAA). To determine whether the endogenous overexpression of APP can also result in vascular cell damage, plasmids containing wild type APP cDNA or a Dutch mutant variant (associated with CAA) under the control of the CMV promoter were stably introduced into bovine aortic endothelial cells and bovine smooth muscle cells. Approximately 10 days post transfection a significant morphological change was observed in endothelial cells expressing either wild type or mutant APP cDNA. These cells exhibited a large number of vacuoles followed by gradual cell death. The cell viability assay confirmed these observations and demonstrated the toxic effect of the amyloid expression in endothelial cells. We observed no toxicity of endothelial cells transfected with a control plasmid containing the β-globin gene. The APP expression in endothelial cells was accompanied by an increase in generation of free radicals that was detected by using fluorescent dye (DCFH-DA). In striking contrast the expression of the wild type or mutant APP in smooth muscle cells had no observed toxic effects, even when cells were maintained in culture as long as 3 months post transfection. Similar expression of the APP proteins in both transfected endothelial and smooth muscle cells was confirmed by immunohistochemistry. Thus the endothelial and smooth muscle cell components of the vasculature differentially respond to an endogenous overexpression of amyloid precursor protein.

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Experimental Hematology







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