Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer’s disease

Tijn, Paula van; Dennissen, Frank J.A.; Gentier, Romina J.G.; Hobo, Barbara; Hermes, Denise; Steinbusch, Harry W.M.; Leeuwen, Fred W. van; Fischer, David F.

doi:10.1016/j.neuint.2012.07.007

Cited by 38 publications

(42 citation statements)

References 46 publications

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“…19 It is reasonable to presume that this inhibition of 26S proteasome would affect degradation of Abeta, leading to abnormal Abeta accumulation. Surprisingly, in the research of van Tijn et al 20 , however, a significant decrease in Abeta deposition and soluble Abeta42 was observed in APPPS1/UBB(z1) transgenic mice compared with in APPPS1 mice at 6 months of age. In other words, UBB(z1) decreases Abeta plaque formation in this transgenic mouse model of AD.…”

Section: Amyloid-beta and Ubiquitination Mutant Ub And Ubiquilinmentioning

confidence: 77%

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

Liang

Huang

Jiang

2014

Neurological Research

126

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Amyloid-beta (Abeta) peptide is the original causative factor of Alzheimer's disease (AD) according to the amyloid cascade hypothesis. The ubiquitin-proteasome system (UPS), the major intracellular protein quality control system in eukaryotic cells, is related to AD pathogenesis. There is growing evidence showing that there is a tight relationship between Abeta and UPS and this relationship plays an important role in AD pathogenesis. This article reviews the relationship between Abeta and the UPS in terms of the following three aspects: the interaction of the two factors, the ubiquitinating process of Abeta, and impact of dysfunctional UPS on Abeta production. The impairment in the UPS in AD could affect the degradation of Abeta and lead to an abnormal accumulation of Abeta. At the same time, Abeta inhibits the proteasomal activity and subsequently leads to impairment of multivesicular bodies (MVB) sorting pathway, forming an interacting relationship between Abeta and UPS. Mutant ubiquitin (Ub) and ubiquitin-like (UBL) ubiquilin-1 are related to Abeta accumulation. Meanwhile E2 conjugating enzymes, E3 ligases, and de-ubiquitinating enzymes, all of which function in the ubiquitination process, play a pivotal role in the proteasomal degradation of Abeta. Ubiquitin-proteasome system has an immense impact on the amyloidogenic pathway of amyloid precursor protein (APP) processing that generates Abeta. Upregulation in proteasomal degradation of BACE1 and components of gamma-secretase leads to decreased Abeta accumulation. A deep look into the mechanism underlying the interplay between Abeta and UPS may provide alternative therapeutic targets and lead to new drugs and therapies.

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Section: Amyloid-beta and Ubiquitination Mutant Ub And Ubiquilinmentioning

confidence: 77%

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

Liang

Huang

Jiang

2014

Neurological Research

126

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“…Similarly, AD-associated mutations in the β-Amyloid precursor protein (APP) or the γ-secretase components presenilin 1 or 2, which are pivotally involved in β-Amyloid generation from APP, do also not fully recapitulate the key pathological events of AD (Nisbet et al, 2015). In order to mimic simultaneously more than one pathological aspect of AD double and triple transgenic AD mouse models or AD patient-derived neuronal stem-cell-derived three-dimensional culture systems have been developed (van Tijn et al, 2012; Choi et al, 2014; Nisbet et al, 2015). …”

Section: Yeast Models Expressing Neurotoxic Proteinsmentioning

confidence: 99%

“…Despite of the UBB +1 -triggered UPS impairment, both yeast and mammalian cells can tolerate UBB +1 without marked signs of cytotoxicity (Hope et al, 2003; van Tijn et al, 2007, 2012; Tank and True, 2009; Yim et al, 2014), and in some cases UBB +1 expression was even protective when mammalian cells were treated with chemicals inducing oxidative stress (Hope et al, 2003; Yim et al, 2014). Consistently, transgenic expression of UBB +1 in mice failed to cause overt neurodegeneration although it did affect spatial reference memory and caused a central dysfunction of respiratory regulation (Fischer et al, 2009; van Tijn et al, 2011; Irmler et al, 2012).…”

Section: Yeast Models Expressing Neurotoxic Proteinsmentioning

confidence: 99%

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Braun

2015

Front. Mol. Neurosci.

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Critically impaired protein degradation is discussed to contribute to neurodegenerative disorders, including Parkinson's, Huntington's, Alzheimer's, and motor neuron diseases. Misfolded, aggregated, or surplus proteins are efficiently degraded via distinct protein degradation pathways, including the ubiquitin-proteasome system, autophagy, and vesicular trafficking. These pathways are regulated by covalent modification of target proteins with the small protein ubiquitin and are evolutionary highly conserved from humans to yeast. The yeast Saccharomyces cerevisiae is an established model for deciphering mechanisms of protein degradation, and for the elucidation of pathways underlying programmed cell death. The expression of human neurotoxic proteins triggers cell death in yeast, with neurotoxic protein-specific differences. Therefore, yeast cell death models are suitable for analyzing the role of protein degradation pathways in modulating cell death upon expression of disease-causing proteins. This review summarizes which protein degradation pathways are affected in these yeast models, and how they are involved in the execution of cell death. I will discuss to which extent this mimics the situation in other neurotoxic models, and how this may contribute to a better understanding of human disorders.

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“…Amyloid deposits and neurofibrillary tangles, comprising hyper phosphorylated tau protein, are the most important pathologic hallmarks of AD. Aβ deposition and clearance are finely regulated by the ubiquitin–proteasome system (UPS) and autophagy, which are tightly interrelated 1–4 . Impairment of proteolysis, which is characteristic of AD neurons, favors the accumulation of detrimental Aβ oligomeric structures that further contribute to proteasome and autophagy alterations.…”

Section: Introductionmentioning

confidence: 99%

Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels

Bonfili

Cecarini

Berardi

et al. 2017

Sci Rep

341

283

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Gut microbiota has a proven role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Oral bacteriotherapy thus has potential in the treatment of central nervous system-related pathologies, such as Alzheimer’s disease (AD). Current AD treatments aim to prevent onset, delay progression and ameliorate symptoms. In this work, 3xTg-AD mice in the early stage of AD were treated with SLAB51 probiotic formulation, thereby affecting the composition of gut microbiota and its metabolites. This influenced plasma concentration of inflammatory cytokines and key metabolic hormones considered therapeutic targets in neurodegeneration. Treated mice showed partial restoration of two impaired neuronal proteolytic pathways (the ubiquitin proteasome system and autophagy). Their cognitive decline was decreased compared with controls, due to a reduction in brain damage and reduced accumulation of amyloid beta aggregates. Collectively, our results clearly prove that modulation of the microbiota induces positive effects on neuronal pathways that are able to slow down the progression of Alzheimer’s disease.

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Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer’s disease

Cited by 38 publications

References 46 publications

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels

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