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

M. LOPEZ SALON, L. PASQUINI, M. BESIO MORENO, J.M. PASQUINI, AND E. SOTO*

EXPERIMENTAL NEUROLOGY

Elsevier Science (USA).

Año: 2003 vol. 180 p. 131 - 143

0014-4886

b-Amyloid peptide (Ab) 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 Ab and the effect of Ab 1–42 and of the fragment Ab 25–35 upon neural cells. We have found that Ab25–35 and Ab1–42 produce a significant increase in Ub–protein conjugates and in the expression of the Ub-activating enzyme E1. On the other hand, _ 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 Ab1–42 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 Ab produced a significant decrease in cell viability, possibly as a consequence of the inhibition of Ab 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 Ab, leading to an abnormal accumulation of Ab 1–42.