The Effect of Aß1₋42 Oligomers on APP Processing and Aß1₋40 Generation in Cultured U-373 Astrocytes.

ABSTRACT

BACKGROUND: Amyloid-ß (Aß) 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 ß- and x03B3;-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aß levels which, in turn, contribute to neuronal loss and development of AD. OBJECTIVES: In this study, we seek to determine what effect Aß has on APP processing in cultured astrocytes. METHODS: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aß1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and ßCTF, and Aß1-40. In conjunction with these experiments, we examined the relative levels and activity of ß- and x03B3;-secretases in Aß-treated astrocytes. RESULTS: We report here that Aß1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aß1-40 in a time-dependent manner. CONCLUSIONS: 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 Aß-related peptides.