Elegans Alzheimer's Disease Model Research Articles

Neuroprotective effect of biogenically synthesized ZnO nanoparticles against oxidative stress and β-amyloid toxicity in transgenic Caenorhabditis elegans.

Amyloid β (Aβ) plaque accumulation-mediated neuronal toxicity has been suggested to cause synaptic damage and consequent degeneration of brain cells in Alzheimer's disease (AD). With the increasing prerequisite of eco-friendly nanoparticles (NPs), research investigators are utilizing green approaches for the synthesis of zinc oxide (ZnO) NPs for pharmaceutical applications. In this present study, ZnO NPs were synthesized from Acanthus ilicifolius to assess the neuroprotective properties in the AD model of transgenic Caenorhabditis elegans strains CL2006 and CL4176 expressing Aβ aggregation. Our findings revealed that the therapeutic effect of green-synthesized ZnO NPs is associated with antioxidant activity. We also found that ZnO NPs significantly enhance the C. elegan's lifespan, locomotion, pharyngeal pumping, chemotaxis behavior also diminish the ROS deposition and intracellular productionMoreover, thioflavin T staining demonstrated that ZnO NPs substantially attenuated the Aβ deposition in the C. elegans strain as compared to untreated worms. With their antioxidant properties, the greenly synthesized ZnO NPs had a significant neuroprotective efficiency on Aβ-induced toxicity by reducing Aβ aggregation and specifically reducing the progression of paralysis in the C. elegans AD model. Our findings suggested that the biosynthesized ZnO NPs could be thought-provoking candidates for age-associated neurodegenerative disorders accompanied by oxidative stress.

αS1-Casein-Loaded Proteo-liposomes as Potential Inhibitors in Amyloid Fibrillogenesis: In Vivo Effects on a C. elegans Model of Alzheimer's Disease.

According to the amyloid hypothesis, in the early phases of Alzheimer's disease (AD), small soluble prefibrillar aggregates of the amyloid β-peptide (Aβ) interact with neuronal membranes, causing neural impairment. Such highly reactive and toxic species form spontaneously and transiently in the amyloid building pathway. A therapeutic strategy consists of the recruitment of these intermediates, thus preventing aberrant interaction with membrane components (lipids and receptors), which in turn may trigger a cascade of cellular disequilibria. Milk αs1-Casein is an intrinsically disordered protein that is able to inhibit Aβ amyloid aggregation in vitro, by sequestering transient species. In order to test αs1-Casein as an inhibitor for the treatment of AD, it needs to be delivered in the place of action. Here, we demonstrate the use of large unilamellar vesicles (LUVs) as suitable nanocarriers for αs1-Casein. Proteo-LUVs were prepared and characterized by different biophysical techniques, such as multiangle light scattering, atomic force imaging, and small-angle X-ray scattering; αs1-Casein loading was quantified by a fluorescence assay. We demonstrated on a C. elegans AD model the effectiveness of the proposed delivery strategy in vivo. Proteo-LUVs allow efficient administration of the protein, exerting a positive functional readout at very low doses while avoiding the intrinsic toxicity of αs1-Casein. Proteo-LUVs of αs1-Casein represent an effective proof of concept for the exploitation of partially disordered proteins as a therapeutic strategy in mild AD conditions.

Protective effect of Gastrodia elata Blume in a Caenorhabditis elegans model of Alzheimer's disease based on network pharmacology.

The aim of the present study was to investigate the protective effect of Gastrodia elata Blume (GEB) against Caenorhabditis elegans (C. elegans) in Alzheimer's disease (AD) through network pharmacology. Firstly, the active constituents of GEB through ETCM and BATMAN-TCM databases were collected and its potential AD-related targets in Swiss Target Prediction were predicted. The potential targets related to AD were collected from the GeneCards, OMIM, CTD and DisGeNET databases, and the differential genes (DEGs) between the normal population and the AD patient population in GSE5281 chip of the Gene Expression Omnibus database were collected at the same time. The intersection of the three targets yielded 59 key targets of GEB for the treatment of AD. The drug-active ingredient-target-AD network diagram was constructed and visualized with Cytoscape software to obtain the core components. Subsequently, protein-protein interaction analysis (PPI) was performed on 59 key targets through STRING database, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses was performed on 59 key targets. Finally, molecular docking was conducted between core components and core targets using AutoDock software, and the C. elegans AD model was used for experimental verification to explore the regulatory paralysis effect of core components on the C. elegans model, β-amyloid (Aβ) plaque deposition, and quantitative polymerase chain reaction verification of the regulatory effect of components on targets. The GEB components 4,4'-dihydroxydiphenyl methane (DM) and protocatechuic aldehyde (PA) were found to be most strongly associated with AD, and five core targets were identified in the PPI network, including GAPDH, EP300, HSP90AB1, KDM6B, and CREBBP. In addition to GAPDH, the other four targets were successfully docked with DM and PA using AutoDock software. Compared with the control group, 0.5 mM DM and 0.25 mM PA significantly delayed C. elegans paralysis (P<0.01), and inhibited the aggregation of Aβ plaques in C. elegans. Both DM and PA could upregulate the expression level of core target gene HSP90AB1 (P<0.01), and DM upregulated the expression of KDM6B (P<0.01), suggesting that DM and PA may be potential active components of GEB in the treatment of AD.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.

Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aβ aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aβ. Moreover, certain azapeptides disassembled preformed Aβ fibrils and protected cells from Aβ-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.

A mechanosensory defect in a C. elegans amyloid-beta glutamatergic neuron model is reversed following exposure to Salvia species extracts.

Previous research has described promising neuroprotective and/or antioxidant properties for extracts derived from a few Salvia (sage) species. Here, six new Salvia species were isolated during flowering times from plants native to Turkey. Extracts were prepared and then examined for their potential to rescue both anterior and posterior mechanosensory behavioral defects in a transgenic C. elegans Alzheimer's disease model that expresses human amyloid-beta (Aβ) peptide (1-42) exclusively in the glutamatergic neurons. Extracts from all six Salvia species rescued anterior touch response defects while only three rescued posterior touch response defects, compared to the Aβ controls.

Effect of Cannabidiol on the Neural Glyoxalase Pathway Function and Longevity of Several C. elegans Strains Including a C. elegans Alzheimer's Disease Model.

Cannabidiol is a nonpsychoactive phytocannabinoid produced by the Cannabis sativa plant and possesses a wide range of pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective activities. Cannabidiol functions in a neuroprotective manner, in part through the activation of cellular antioxidant pathways. The glyoxalase pathway detoxifies methylglyoxal, a highly reactive metabolic byproduct that can accumulate in the brain, and contributes to the severity of neurodegenerative diseases, including Alzheimer's disease. While cannabidiol's antioxidant properties have been investigated, it is currently unknown how it may modulate the glyoxalase pathway. In this research paper, we examine the effects of Cannabidiol on cerebellar neurons and in several Caenorhabditis elegans strains. We determined that a limited amount of Cannabidiol can prevent methylglyoxal-mediated cellular damage through enhancement of the neural glyoxalase pathway and extend the lifespan and survival of C. elegans, including a transgenic C. elegans strain modeling Alzheimer's disease.

Epibrassinolide prevents tau hyperphosphorylation via GSK3β inhibition in vitro and improves Caenorhabditis elegans lifespan and motor deficits in combination with roscovitine.

Glycogen synthase kinase 3β (GSK3β) is considered an important element of glycogen metabolism; however, it has many other regulatory roles. Changes in the GSK3β signaling mechanism have been associated with various disorders, such as Alzheimer's disease (AD), type II diabetes, and cancer. Although the effects of GSK3β inhibitors on reducing the pathological effects of AD have been described, an effective inhibitor has not yet been developed. Epibrassinolide (EBR), a brassinosteroid (BR), is structurally similar to mammalian steroid hormones. Our studies have shown that EBR has an inhibitory effect on GSK3β in different cell lines. Roscovitine (ROSC), a cyclin-dependent kinase (CDK) inhibitor, has also been identified as a potential GSK3 inhibitor. Within the scope of this study, we propose that EBR and/or ROSC might have mechanistic action in AD models. To test this hypothesis, we used in vitro models and Caenorhabditis elegans (C. elegans) AD strains. Finally, EBR treatment successfully protected cells from apoptosis and increased the inhibitory phosphorylation of GSK3β. In addition, EBR and/or ROSC treatment had a positive effect on the survival rates of C. elegans strains. More interestingly, the paralysis phenotype of the C. elegans AD model due to Aβ42 toxicity was prevented by EBR and/or ROSC. Our findings suggest that EBR and ROSC administration have neuroprotective effects on both in vitro and C. elegans models via inhibitory GSK3β phosphorylation at Ser9.

Bacillus Subtilis Delays Neurodegeneration and Behavioral Impairment in the Alzheimer's Disease Model Caenorhabditis Elegans.

Multiple causes, apart from genetic inheritance, predispose to the production and aggregation of amyloid-β (Aβ) peptide and Alzheimer's disease (AD) development in the older population. There is currently no therapy or medicine to prevent or delay AD progression. One novel strategy against AD might involve the use of psychobiotics, probiotic gut bacteria with specific mental health benefits. Here, we report the neuronal and behavioral protective effects of the probiotic bacterium Bacillus subtilis in a Caenorhabditis elegans AD model. Aging and neuronal deterioration constitute important risk factors for AD development, and we showed that B. subtilis significantly delayed both detrimental processes in the wild-type C. elegans strain N2 compared with N2 worms colonized by the non-probiotic Escherichia coli OP50 strain. Importantly, B. subtilis alleviated the AD-related paralysis phenotype of the transgenic C. elegans strains CL2120 and GMC101 that express, in body wall muscle cells, the toxic peptides Aβ3-42 and Aβ1-42, respectively. B. subtilis-colonized CL2355 worms were protected from the behavioral deficits (e.g., poor chemotactic response and decreased body bends) produced by pan-neuronal Aβ1-42 expression. Notably, B. subtilis restored the lifespan level of C. elegans strains that express Aβ to values similar to the life expectancy of the wild-type strain N2 fed on E. coli OP50 cells. The B. subtilis proficiencies in quorum-sensing peptide (i.e., the Competence Sporulation Factor, CSF) synthesis and gut-associated biofilm formation (related to the anti-aging effect of the probiotic) play a crucial role in the anti-AD effects of B. subtilis. These novel results are discussed in the context of how B. subtilis might exert its beneficial effects from the gut to the brain of people with or at risk of developing AD.

The protection of novel 2-arylethenylquinoline derivatives against impairment of associative learning memory induced by neural Aβ in C. elegans Alzheimer's disease model.

Cerebral deposition of amyloid β-peptide (Aβ), a fundamental feature of Alzheimer's disease (AD), damages the neurocytes and impairs the cognition functions and associative learning memory of AD patients. A series of novel 2-arylethenylquinoline derivatives were synthesized and evaluated in our previous study, which inhibited Aβ aggregation in vitro effectively at the concentration of 20μmol/L and exhibited high antioxidant activity. In order to verify the capacity of anti-AD in vivo, the transgenic Caenorhabditis elegans (C. elegans) strain CL2355 expressing neural Aβ was employed as the AD model to investigate the neuroprotective activity of seven high-potential compounds (4a1, 4a2, 4b1, 4b2, 4c1, 4c2, 4c3) selected from those derivatives. Learning memory associated chemotaxis assay was performed to evaluate the neural repairment capacity. The underlying mechanism was investigated by mRNA analysis of Aβ gene and heat shock protein genes (hsp-16.1 and hsp-16.2) and Western blot of Aβ. Our data indicated that among seven tested compound, 4b1 and 4c2 reduced Aβ-induced stress, suppressed the expression of neural Aβ monomers and toxic oligomers, and recovered the damaged associative learning memory in C. elegans AD model. These findings further confirmed their potentials to become valuable agents for AD therapy.

Peptide multifunctionalized gold nanorods decrease toxicity of β-amyloid peptide in a Caenorhabditis elegans model of Alzheimer's disease

The properties of nanometric materials make nanotechnology a promising platform for tackling problems of contemporary medicine. In this work, gold nanorods were synthetized and stabilized with polyethylene glycols and modified with two kinds of peptides. The D1 peptide that recognizes toxic aggregates of Aβ, a peptide involved in Alzheimer's disease (AD); and the Angiopep 2 that can be used to deliver nanorods to the mammalian central nervous system. The nanoconjugates were characterized using absorption spectrophotometry, dynamic light scattering, and transmission electron microscopy, among other techniques. We determined that the nanoconjugate does not affect neuronal viability; it penetrates the cells, and decreases aggregation of Aβ peptide in vitro. We also showed that when we apply our nanosystem to a Caenorhabditis elegans AD model, the toxicity of aggregated Aβ peptide is decreased. This work may contribute to the development of therapies for AD based on metallic nanoparticles.

Cranberry extract supplementation exerts preventive effects through alleviating Aβ toxicity in Caenorhabditis elegans model of Alzheimer's disease

Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Aβ toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Aβ toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals.

Cranberry Extract Standardized for Proanthocyanidins Alleviates β-Amyloid Peptide Toxicity by Improving Proteostasis Through HSF-1 in Caenorhabditis elegans Model of Alzheimer's Disease.

A growing body of evidence suggests that nutraceuticals with prolongevity properties may delay the onset of Alzheimer's disease (AD). We recently demonstrated that a proanthocyanidins-standardized cranberry extract has properties that prolong life span and promote innate immunity in Caenorhabditis elegans In this article, we report that supplementation of this cranberry extract delayed Aβ toxicity-triggered body paralysis in the C elegans AD model. Genetic analyses indicated that the cranberry-mediated Aβ toxicity alleviation required heat shock transcription factor (HSF)-1 rather than DAF-16 and SKN-1. Moreover, cranberry supplementation increased the transactivity of HSF-1 in an IIS-dependent manner. Further studies found that the cranberry extract relies on HSF-1 to significantly enhance the solubility of proteins in aged worms, implying an improved proteostasis in AD worms. Considering that HSF-1 plays a pivotal role in maintaining proteostasis, our results suggest that cranberry maintains the function of proteostasis through HSF-1, thereby protecting C elegans against Aβ toxicity. Together, our findings elucidated the mechanism whereby cranberry attenuated Aβ toxicity in C elegans and stressed the significance of proteostasis in the prevention of age-related diseases from a practical point of view.

Identifying Aβ-specific pathogenic mechanisms using a nematode model of Alzheimer's disease

Multiple gene expression alterations have been linked to Alzheimer's disease (AD), implicating multiple metabolic pathways in its pathogenesis. However, a clear distinction between AD-specific gene expression changes and those resulting from nonspecific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human beta-amyloid peptide (Aβ) in a Caenorhabditis elegans AD model. Aβ-induced gene expression alterations were compared with those caused by a synthetic aggregating protein to identify Aβ-specific effects. Both Aβ-specific and nonspecific alterations were observed. Among Aβ-specific genes were those involved in aging, proteasome function, and mitochondrial function. An intriguing observation was the significant overlap between gene expression changes induced by Aβ and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that Aβ exerts its toxic effect, at least in part, by causing damage to biological membranes. We provide in vivo evidence consistent with this hypothesis. This study distinguishes between Aβ-specific and nonspecific mechanisms and provides potential targets for therapeutics discovery.

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

Epidemiological studies have reported that coffee and/or caffeine consumption may reduce Alzheimer's disease (AD) risk. We found that coffee extracts can similarly protect against β-amyloid peptide (Aβ) toxicity in a transgenic Caenorhabditis elegans Alzheimer's disease model. The primary protective component(s) in this model is not caffeine, although caffeine by itself can show moderate protection. Coffee exposure did not decrease Aβ transgene expression and did not need to be present during Aβ induction to convey protection, suggesting that coffee exposure protection might act by activating a protective pathway. By screening the effects of coffee on a series of transgenic C. elegans stress reporter strains, we identified activation of the skn-1 (Nrf2 in mammals) transcription factor as a potential mechanism of coffee extract protection. Inactivation of skn-1 genetically or by RNAi strongly blocked the protective effects of coffee extract, indicating that activation of the skn-1 pathway was the primary mechanism of coffee protection. Coffee also protected against toxicity resulting from an aggregating form of green fluorescent protein (GFP) in a skn-1-dependent manner. These results suggest that the reported protective effects of coffee in multiple neurodegenerative diseases may result from a general activation of the Nrf2 phase II detoxification pathway.

AIP-1 ameliorates β-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model

Multiple neurodegenerative diseases are causally linked to aggregation-prone proteins. Cellular mechanisms involving protein turnover may be key defense mechanisms against aggregating protein disorders. We have used a transgenic Caenorhabditis elegans Alzheimer's disease model to identify cellular responses to proteotoxicity resulting from expression of the human beta amyloid peptide (Abeta). We show up-regulation of aip-1 in Abeta-expressing animals. Mammalian homologues of AIP-1 have been shown to associate with, and regulate the function of, the 26S proteasome, leading us to hypothesize that induction of AIP-1 may be a protective cellular response directed toward modulating proteasomal function in response to toxic protein aggregation. Using our transgenic model, we show that overexpression of AIP-1 protected against, while RNAi knockdown of AIP-1 exacerbated, Abeta toxicity. AIP-1 overexpression also reduced accumulation of Abeta in this model, which is consistent with AIP-1 enhancing protein degradation. Transgenic expression of one of the two human aip-1 homologues (AIRAPL), but not the other (AIRAP), suppressed Abeta toxicity in C. elegans, which advocates the biological relevance of the data to human biology. Interestingly, AIRAPL and AIP-1 contain a predicted farnesylation site, which is absent from AIRAP. This farnesylation site was shown by others to be essential for an AIP-1 prolongevity function. Consistent with this, we show that an AIP-1 mutant lacking the predicted farnesylation site failed to protect against Abeta toxicity. Our results implicate AIP-1 in the regulation of protein turnover and protection against Abeta toxicity and point at AIRAPL as the functional mammalian homologue of AIP-1.