Impaired Proteasome Function in Alzheimer's Disease

Abstract

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 protein carbonyls in the mutant transfectants could be related to impaired proteasomal function as well as to the observed rise in lipid peroxidation, because protein carbonyls can arise from direct oxidative damage to certain amino acid residues and/or by the binding of certain aldehyde end products of lipid peroxidation to proteins (22,58). Indeed, we reported marked increase in iron accumulation in the substantia nigra of AR-JP brains, indicating that oxidative stress appears to play an important role on nigral cell death in AR-JP (59).…”

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

“…Recent studies from our group and others demonstrated that disturbance of proteolytic machinery is a key feature of degenerating neurons and appears in several neurodegenerative disorders (4,8,15). Proteasome activity was found to be reduced in AD brains than in age-matched controls (38,50) and also in DS brain (17). In addition, high levels of Ub were detected in brain and cerebrospinal fluid samples from AD patients (43).…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Thus, oxidative inactivation of UCH-L1 possibly contributes to both protein aggregation and OS observed in AD brain. Moreover, UCH-L1 oxidative dysfunction could affect activity of the 26S proteasome, which is known to be altered in AD (221). Thus, these pathophysiological observations in AD brain may be related to oxidized UCH-L1: brain protein with excess ubiquitinylation, decreased activity of the 26S proteaome, and consequent accumulation of aggregated, damaged proteins.…”