Relationship between β-amyloid degradation and the 26S proteasome in neural cells

Abstract

β-Amyloid peptide (Aβ) plays a central role in mediating neurotoxicity and in the formation of senile plaques in Alzheimer’s disease (AD). The investigation of the roles of ubiquitin (Ub) in the process underlying the association of abnormal protein with the inclusion bodies that characterize AD is of great importance for the further understanding of this disorder. We have used primary cultures of cortical neurons and astrocytes to investigate the participation of the Ub–proteasome pathway in the degradation of Aβ and the effect of Aβ 1–42 and of the fragment Aβ 25–35 upon neural cells. We have found that Aβ 25–35 and Aβ 1–42 produce a significant increase in Ub–protein conjugates and in the expression of the Ub-activating enzyme E1. On the other hand, β peptides inhibited the proteolytic activities of the 26S proteasome. When the proteolytic activity of the 26S proteasome was inhibited with lactacystin, there was a marked decrease in Aβ 1–42 degradation, suggesting that the peptide, in both astrocytes and neurons, could be a possible substrate of this enzymatic complex. Treatment of the cultures with lactacystin prior to the exposure to Aβ produced a significant decrease in cell viability, possibly as a consequence of the inhibition of Aβ degradation leading to a persistent exposure of the cells to the amyloidogenic peptide which results in cell death. Alterations in the Ub–proteasome pathway in AD could affect the normal proteolytic removal of Aβ, leading to an abnormal accumulation of Aβ 1–42.