Amyloid-β Increases Activity of Proteasomes Capped with 19S and 11S Regulators

Abstract

Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer's disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes.

Interplay between recombinant Hsp70 and proteasomes: proteasome activity modulation and ubiquitin-independent cleavage of Hsp70

“…2bd). These data are also in line with our and previous findings by others where decrease of the pure 20S proteasome activity following incubation with different Aβ peptides was demonstrated (Morozov 2016;Tseng et al 2008;Zhao and Yang 2010). However, Zhao and Yang have shown that Aβ is a substrate of 20S proteasome and observed proteasome inhibition results from protein and fluorogenic peptide competition for the active sites of the proteasome (Zhao and Yang 2010).…”

“…On the other hand, the 20S fraction contains large amount of proteasomes with 11S regulators ( Fig. 3g) (Morozov 2016), which represent the most catalytically active form of proteasome in this fraction (Morozov 2016). Keeping in mind very low amount of 26S proteasomes in the 20S fraction (Fig.…”

“…Keeping in mind very low amount of 26S proteasomes in the 20S fraction (Fig. 1c) (Morozov 2016) and decrease of the activity of purified 20S proteasomes following Hsp70 treatment (Fig. 2b, c), it is very likely that the increased proteasome activity in this fraction is mediated via another form of proteasome: 20S proteasomes with 11S regulators.…”

“…The activation of 26S proteasomes by Hsp70 is in line with our previous findings. Recently, we demonstrated that amyloid-beta (Aβ) peptide induces a concentrationdependent increase of 26S proteasome activity (at least regarding fluorogenic peptide degradation) (Morozov 2016). The effect was attributed to the possible interaction of the peptide with the 19S proteasome regulator.…”

“…Fractionation of the proteasomes from Kasumi-1 cells was performed as described (Morozov 2016) on the basis of the technique published by Abramova et al (2004). In brief, cells were lysed and centrifuged at 16,100×g for 30 min.…”