Amyloid-β peptide is a substrate of the human 20S proteasome.

Intraneuronal accumulation of ubiquitin conjugates is a pathological feature of neurodegenerative disorders such as Alzheimer's disease (AD). Previous reports propose that accumulation of ubiquitinated species in AD is a result of inhibition of proteasomal activity by amyloid-β (Aβ) peptides, which leads to blocking of ubiquitin-dependent protein degradation by the proteasome. Here, we provide additional insight into proteasomal dysfunction by Aβ peptides by revealing that aggregated forms of Aβ(1-42) peptides (especially small oligomers) are, in fact, competitive substrates for the chymotrypsin-like activity of the human 20S (h20S) proteasome. In addition to examining the kinetics of the h20S proteasome activity in the presence or absence of Aβ peptides, we use gel electrophoresis, LC-MS, and TOF-MS/MS analyses to examine the degradation of Aβ(1-42) by the h20S proteasome. The observed peptide fragments resulting from proteolytic cleavage of Aβ were consistent with predicted cleavage sites from proteasome degradation. These results support that the interaction of Aβ peptides with the proteasome may play a mechanistic role in proteasomal dysfunction in AD pathology. These results may also reveal a previously unknown natural pathway for clearance of Aβ in normal or diseased cells.