The Effect of Aβ_1-42 Oligomers on APP Processing and Aβ_1-40 Generation in Cultured U-373 Astrocytes

Abstract

<b><i>Background:</i></b> Amyloid-β (Aβ) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via β- and &#947;-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aβ levels which, in turn, contribute to neuronal loss and development of AD. <b><i>Objectives:</i></b> In this study, we seek to determine what effect Aβ has on APP processing in cultured astrocytes. <b><i>Methods:</i></b> Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aβ_1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and βCTF, and Aβ_1-40. In conjunction with these experiments, we examined the relative levels and activity of β- and &#947;-secretases in Aβ-treated astrocytes. <b><i>Results:</i></b> We report here that Aβ_1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aβ_1-40 in a time-dependent manner. <b><i>Conclusions:</i></b> These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Aβ-related peptides.