| First Author | Verheijen BM | Year | 2018 |
| Journal | Neurobiol Aging | Volume | 72 |
| Pages | 62-71 | PubMed ID | 30216939 |
| Mgi Jnum | J:271510 | Mgi Id | MGI:6279440 |
| Doi | 10.1016/j.neurobiolaging.2018.08.011 | Citation | Verheijen BM, et al. (2018) Paradoxical effects of mutant ubiquitin on Abeta plaque formation in an Alzheimer mouse model. Neurobiol Aging 72:62-71 |
| abstractText | Amyloid-beta (Abeta) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Abeta peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Abeta-associated factors. Efficient clearance of Abeta 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 Abeta pathology in vivo, transgenic APPSwe/PS1DeltaE9 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 Abeta plaque load during aging. Further analysis showed that UBB(+1) expression transiently restored PS1-NTF expression and gamma-secretase activity in APPPS1 mice. Concurrently, UBB(+1) decreased levels of beta-APP-CTF, which is a gamma-secretase substrate. Although UBB(+1) reduced Abeta pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals. |
