Inhibition of proteasome activity is sufficient to induce neuron degeneration and death; however, altered proteasome activity in a neurodegenerative disorder has not been demonstrated. In the present study, we analyzed proteasome activity in shortpostmortem-interval autopsied brains from 16 Alzheimer's disease (AD) and nine age-and sex-matched controls. A significant decrease in proteasome activity was observed in the hippocampus and parahippocampal gyrus (48%), superior and middle temporal gyri (38%), and inferior parietal lobule (28%) of AD patients compared with controls. In contrast, no significant decrease in proteasome activity was observed in either the occipital lobe or the cerebellum. The loss of proteasome activity was not associated with a decrease in proteasome expression, suggesting that the proteasome may become inhibited in AD by a posttranslational modification. Together, these data indicate a possible role for proteasome inhibition in the neurodegeneration associated with AD. Key Words: Alzheimer's disease-Amyloid ␤-peptide-Neurodegeneration-Oxidative stress-Proteasome-Ubiquitin. J. Neurochem. 75, 436 -439 (2000).The proteasome is a large, ϳ700-kDa complex, which is present in all cells of the CNS (Coux et al., 1996;Tanaka, 1998;Tanaka and Chiba, 1998). The proteasome is composed of 28 individual ␣-and ␤-subunits, which are arranged in four rings, with each ring composed of either seven ␣-or seven ␤-subunits. The two inner rings of the proteasome are composed of the ␤-subunits, which possess the proteolytic sites, whereas the ␣-subunits function to stabilize the proteasome complex. Caplike structures can bind to the 20S proteasome to form a larger, ϳ2,000-kDa 26S proteasome complex. The proteasome is responsible for the majority of cellular proteolysis (Rock et al., 1994) and has been best characterized for its role in the ubiquitin-ATP-dependent proteolytic pathway (Hershko and Ciechanover, 1992). In addition to ubiquitinated proteins, the proteasome degrades multiple substrates that are important in maintaining neuronal homeostasis, including the catabolism of oxidized, damaged, and aggregated proteins (Grune et al., 1997;Tanaka, 1998;Tanaka and Chiba, 1998). Since its discovery, the proteasome has been demonstrated in several cellular functions, including differentiation, proliferation, and apoptosis (Tanaka, 1998;Tanaka and Chiba, 1998); however, the role of the proteasome in the CNS has not been determined.Recent studies implicate a possible role for proteasome inhibition in neuron degeneration and death that occurs in Alzheimer's disease (AD). Proteasome activity is inhibited by the application of amyloid ␤-peptide and exposure to oxidative stress (Gregori et al., 1995;Grune et al., 1995;Reinheckel et al., 1998), both of which are believed to contribute to the progression of AD (Markesbery, 1997;Mattson, 1997). Also, pharmacologic inhibition of the proteasome is sufficient to induce neuron degeneration and death (Lopes et al., 1997;Boutillier et al., 1999;Qiu et al., 2000).In spi...

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Increased levels of reactive oxygen species occur in neurodegenerative disorders and may promote neuron death. The lipid peroxidation product 4-hydroxynonenal (HNE) is increased in neurons following oxidative stress and promotes neuron death in vitro and in vivo. The present study examined the possibility that HNE can increase neuron vulnerability to oxidative stress. Application of low concentrations of HNE (50-500 nM) increased neuron death induced by beta-amyloid or glutamate when added within 3 hr of injury. In addition, treatment with HNE exacerbated mitochondrial reactive oxygen species formation and loss of mitochondrial membrane potential in response to beta-amyloid and glutamate. The ability to exacerbate oxidative stress, mitochondrial dysfunction, and neuron death appears to be specific to HNE, because application of other lipid peroxidation products had no effect. These data indicate a role for low levels of HNE in promoting reactive oxygen species accumulation and neuron degeneration by altering mitochondrial homeostasis. In addition, the present study indicates a possible mechanism for reactive oxygen species and lipid peroxidation toxicity in neurodegenerative conditions.

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