Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model

Amyloid-beta (Ab) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated A beta peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several A beta-associated factors. Efficient clearance of A beta from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Ab pathology in vivo, transgenic APP(Swe)/PS1 Delta E9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Ab plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and g-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of beta-APP-CTF, which is a g-secretase substrate. Although UBB+1 reduced Ab pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals. (C) 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.