Prevention of beta-amyloid neurotoxicity by blockade of the ubiquitin-proteasome proteolytic pathway

In many neurodegenerative disorders, such as Alzheimer's disease, inclusion s containing ubiquitinated proteins have been found in the brain, suggestin g 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 neu rons, also induces the ubiquitination of several neuronal proteins. Prevent ion of ubiquitination and inhibition of proteasome activity block the neuro toxic effect of beta-amyloid. These data suggest that beta-amyloid neurotox icity may cause toxicity through the activation of protein degradation via the ubiquitin-proteasome pathway. These findings suggest possible new pharm acological targets for the prophylaxis and/or treatment of Alzheimer's dise ase and possibly for other related neurodegenerative disorders.