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. 2018 Dec:72:62-71.
doi: 10.1016/j.neurobiolaging.2018.08.011. Epub 2018 Aug 18.

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

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Free article

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

Bert M Verheijen et al. Neurobiol Aging. 2018 Dec.
Free article

Abstract

Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ 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 Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 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 Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals.

Keywords: Alzheimer's disease; Amyloid-β; Behavior; Mutant ubiquitin; Ubiquitin-proteasome system; γ-Secretase.

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  • Mutant ubiquitin reduces Aβ plaques.
    Verheijen BM, van Leeuwen FW. Verheijen BM, et al. Aging (Albany NY). 2018 Oct 15;10(10):2544-2546. doi: 10.18632/aging.101598. Aging (Albany NY). 2018. PMID: 30321138 Free PMC article. No abstract available.

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