Relationship between beta-amyloid degradation and the 26S proteasome in neural cells.
Beta-amyloid peptide (Abeta) 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 Abeta and the effect of Abeta(1-42) and of the fragment Abeta(25-35) upon neural cells. We have found that Abeta(25-35) and Abeta(1-42) produce a significant increase in Ub-protein conjugates and in the expression of the Ub-activating enzyme E1. On the other hand, beta 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 Abeta(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 Abeta produced a significant decrease in cell viability, possibly as a consequence of the inhibition of Abeta 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 Abeta, leading to an abnormal accumulation of Abeta(1-42).
Lopez Salon
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Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológicas, UBA-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina.
Pasquini
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L
Besio Moreno
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M
Pasquini
J M
JM
Soto
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E
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008025:Ligases / Q000378:metabolism; D046911:Macromolecular Substances; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D010446:Peptide Fragments; D025801:Ubiquitin; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C067713:lactacystin; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008025:Ligases; D000111:Acetylcysteine