Prevention of beta-amyloid neurotoxicity by blockade of the ubiquitin-proteasome proteolytic pathway.
In many neurodegenerative disorders, such as Alzheimer's disease, inclusions containing ubiquitinated proteins have been found in the brain, suggesting a pathophysiological role for ubiquitin-mediated proteasomal degradation of neuronal proteins. Here we show for the first time that the beta-amyloid fragment 1-40, which in micromolar levels causes the death of cortical neurons, also induces the ubiquitination of several neuronal proteins. Prevention of ubiquitination and inhibition of proteasome activity block the neurotoxic effect of beta-amyloid. These data suggest that beta-amyloid neurotoxicity may cause toxicity through the activation of protein degradation via the ubiquitin-proteasome pathway. These findings suggest possible new pharmacological targets for the prophylaxis and/or treatment of Alzheimer's disease and possibly for other related neurodegenerative disorders.
Favit
A
A
Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20817, USA.
Grimaldi
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Alkon
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DL
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005333:Fetus; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D009498:Neurotoxins; D010446:Peptide Fragments; D014452:Ubiquitins; C078592:amyloid beta-protein (1-40); C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine