scholarly journals USP14 haploinsufficiency ameliorates Alzheimer’s disease-like pathology in APP/PS1 mice

2020 ◽  
Author(s):  
Hua Xu ◽  
Xueheng Wu ◽  
Lu Liang ◽  
Haoyu Chen ◽  
Jia Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Senile Plaques ◽  
Ubiquitin Proteasome System ◽  
Spatial Learning And Memory ◽  
Protein Levels ◽  
Reported Study ◽  
Ubiquitin Proteasome ◽  
The Impact

Abstract Background: Alzheimer's disease (AD) is the most common cause of dementia; its main pathological features are neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (Tau) in the cell and extracellular beta-amyloid protein (Aβ)-based senile plaques (SP). The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells. Proteasome malfunction exists in AD patients and may promote the progression of the disease. USP14 is a deubiquitinating enzyme associated with the 19S proteasome. Functional inhibition of USP14 was shown to enhance proteasome proteolytic function, but no reported study has investigated the impact of genetic inhibition of USP14 on AD.Methods: Mice with heterozygous knockout of the Usp14 gene (USP14+/-) were generated and cross-bred with the APP/PS1 transgenic mice, the resultant offspring littermates were subjected to basal survival and growth analyses, and comparison of AD-like pathologies as detected with biochemical and histopathological methods and of cognitive function as assessed with the Morris water maze tests. Results:USP14 mRNA and protein levels in USP14+/- mice were decreased by ~50% compared with USP14+/+mice. The increases of total, K48 or K63 linked ubiquitinated proteins in APP/PS1 mouse brains were abolished in APP/PS1::USP14+/- mice. The increases in Aβ deposition and AD-associated phosphorylated Tau, senile plagues and neurofibrillary tangles, as well as spatial learning and memory decline induced by APP/PS1 were significantly attenuated in APP/PS1 mice. Conclusions: This study demonstrates that global knocking down USP14 protein expression by 50% is tolerable by mice and exhibits marked protection against AD-like pathologies in a widely used AD mouse model, favoring the exploration of moderate inhibition ofUSP14 as a potentially novel and viable therapy against AD.

scholarly journals USP14 Haploinsufficiency Ameliorates Alzheimer’s Disease-Like Pathology in APP/PS1 Mice

2020 ◽  
Author(s):  
Hua Xu ◽  
Xueheng Wu ◽  
Lu Liang ◽  
Haoyu Chen ◽  
Jia Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Senile Plaques ◽  
Ubiquitin Proteasome System ◽  
Spatial Learning And Memory ◽  
Protein Levels ◽  
Reported Study ◽  
Ubiquitin Proteasome ◽  
The Impact

Abstract Background: Alzheimer's disease (AD) is the most common cause of dementia; its main pathological features are neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (Tau) in the cell and extracellular beta-amyloid protein (Aβ)-based senile plaques (SP). The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells. Proteasome malfunction exists in AD patients and may promote the progression of the disease. USP14 is a deubiquitinating enzyme associated with the 19S proteasome. Functional inhibition of USP14 was shown to enhance proteasome proteolytic function, but no reported study has investigated the impact of genetic inhibition of USP14 on AD.Methods: Mice with heterozygous knockout of the Usp14 gene (USP14+/-) were generated and cross-bred with the APP/PS1 transgenic mice, the resultant offspring littermates were subjected to basal survival and growth analyses, and comparison of AD-like pathologies as detected with biochemical and histopathological methods and of cognitive function as assessed with the Morris water maze tests. Results:USP14 mRNA and protein levels in USP14+/- mice were decreased by ~50% compared with USP14+/+mice. The increases of total, K48 or K63 linked ubiquitinated proteins in APP/PS1 mouse brains were abolished in APP/PS1::USP14+/- mice. The increases in Aβ deposition and AD-associated phosphorylated Tau, senile plagues and neurofibrillary tangles, as well as spatial learning and memory decline induced by APP/PS1 were significantly attenuated in APP/PS1 mice. Conclusions: This study demonstrates that global knocking down USP14 protein expression by 50% is tolerable by mice and exhibits marked protection against AD-like pathologies in a widely used AD mouse model, favoring the exploration of moderate inhibition ofUSP14 as a potentially novel and viable therapy against AD.

scholarly journals Identification of hub ubiquitin ligase genes affecting Alzheimer’s disease by analyzing transcriptome data from multiple brain regions

2021 ◽  
Vol 104 (1) ◽  
pp. 003685042110011
Author(s):  
Dahai Liu ◽  
Shao-Xing Dai ◽  
Kan He ◽  
Gong-Hua Li ◽  
Justin Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Brain Regions ◽  
Cellular Functions ◽  
Brain Transcriptome ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Proteasome ◽  
The Impact

The ubiquitin-proteasome system (UPS) plays crucial roles in numerous cellular functions. Dysfunction of the UPS shows certain correlations with the pathological changes in Alzheimer’s disease (AD). This study aimed to explore the different impairments of the UPS in multiple brain regions and identify hub ubiquitin ligase (E3) genes in AD. The brain transcriptome, blood transcriptome and proteome data of AD were downloaded from a public database. The UPS genes were collected from the Ubiquitin and Ubiquitin-like Conjugation Database. The hub E3 genes were defined as the differentially expressed E3 genes shared by more than three brain regions. E3Miner and UbiBrowser were used to predict the substrate of hub E3. This study shows varied impairment of the UPS in different brain regions in AD. Furthermore, we identify seven hub E3 genes (CUL1, CUL3, EIF3I, NSMCE1, PAFAH1B1, RNF175, and UCHL1) that are downregulated in more than three brain regions. Three of these genes (CUL1, EIF3I, and NSMCE1) showed consistent low expression in blood. Most of these genes have been reported to promote AD, whereas the impact of RNF175 on AD is not yet reported. Further analysis revealed a potential regulatory mechanism by which hub E3 and its substrate genes may affect transcription functions and then exacerbate AD. This study identified seven hub E3 genes and their substrate genes affect transcription functions and then exacerbate AD. These findings may be helpful for the development of diagnostic biomarkers and therapeutic targets for AD.

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

scholarly journals Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

2000 ◽  
Vol 97 (18) ◽  
pp. 9902-9906 ◽  
Author(s):  
Y. A. Lam ◽  
C. M. Pickart ◽  
A. Alban ◽  
M. Landon ◽  
C. Jamieson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Min-Soo Kim ◽  
Yoonhee Kim ◽  
Hyunjung Choi ◽  
Woojin Kim ◽  
Sumyung Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurofibrillary Tangles ◽  
Immune Cell ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Faecal Microbiota ◽  
Inflammatory Monocytes ◽  
The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

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