scholarly journals Sideritis scardicaextracts inhibit aggregation and toxicity of amyloid-βinCaenorhabditis elegansused as a model for Alzheimer’s disease

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4683 ◽  
Author(s):  
Felix Heiner ◽  
Björn Feistel ◽  
Michael Wink
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pharmacological Activity ◽  
Model Organism ◽  
Amyloid Β ◽  
Ethanolic Extract ◽  
Active Principle ◽  
Head Region ◽  
C Elegans ◽  
Polar Extracts

BackgroundBeyond its traditional uses in the Balkan area,Sideritis scardica(known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts ofS. scardicafor their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer’s disease.MethodsFor this purpose, we have chosen the nematodeCaenorhabditis elegans, which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70% ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40% ethanolic extract and phytochemically analysed.ResultsEssentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenicC. elegansstrains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50% ethanol) turned out be the most active, decreasing the plaque number by 21% and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones.DiscussionSideritis scardicaextracts demonstrated pharmacological activity against characteristics of Alzheimer’s disease also inC. elegans, supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.

scholarly journals Sideritis scardica extracts inhibit aggregation and toxicity of amyloid-β in Caenorhabditis elegans used as a model for Alzheimer's disease

2017 ◽  
Author(s):  
Felix Heiner ◽  
Björn Feistel ◽  
Michael Wink
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Pharmacological Activity ◽  
Model Organism ◽  
Amyloid Β ◽  
Ethanolic Extract ◽  
Active Principle ◽  
Head Region ◽  
C Elegans

Background. Beyond its traditional uses in the Balkan area, Sideritis scardica (known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts of S. scardica for their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer's disease. Methods. For this purpose, we have chosen the nematode Caenorhabditis elegans, which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70 % ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40 % ethanolic extract and phytochemically analysed. Results. Essentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenic C. elegans strains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50 % ethanol) turned out be the most active, decreasing the plaque number by 21 % and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones. Discussion. Sideritis scardica extracts demonstrated pharmacological activity against characteristics of Alzheimer's disease also in C. elegans, supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.

scholarly journals Sideritis scardica extracts inhibit aggregation and toxicity of amyloid-β in Caenorhabditis elegans used as a model for Alzheimer's disease

2017 ◽  
Author(s):  
Felix Heiner ◽  
Björn Feistel ◽  
Michael Wink
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Pharmacological Activity ◽  
Model Organism ◽  
Amyloid Β ◽  
Ethanolic Extract ◽  
Active Principle ◽  
Head Region ◽  
C Elegans

Background. Beyond its traditional uses in the Balkan area, Sideritis scardica (known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts of S. scardica for their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer's disease. Methods. For this purpose, we have chosen the nematode Caenorhabditis elegans, which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70 % ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40 % ethanolic extract and phytochemically analysed. Results. Essentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenic C. elegans strains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50 % ethanol) turned out be the most active, decreasing the plaque number by 21 % and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones. Discussion. Sideritis scardica extracts demonstrated pharmacological activity against characteristics of Alzheimer's disease also in C. elegans, supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

scholarly journals Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

2020 ◽  
Author(s):  
Sanjib Guha ◽  
Sarah Fischer ◽  
Gail VW Johnson ◽  
Keith Nehrke
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Model ◽  
Neurodegenerative Disorder ◽  
Model Organism ◽  
Single Copy ◽  
Mitochondrial Stress ◽  
C Elegans ◽  
Touch Receptor Neurons ◽  
New Perspective

ABSTRACTBackgroundA defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear.MethodsHuman 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E and T231A, to mimic phosphorylation and phospho-ablation of a commonly observed pathological epitope, respectively, and K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age, and genetically-encoded fluorescent biosensors were used to measure the morphological dynamics and turnover of touch neuron mitochondria.ResultsUnlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to mitochondrial stress.ConclusionsLimiting the expression of tau results in a genetic model where pathological modifications and age result in evolving phenotypes, which may more closely resemble the normal progression of AD. The finding that disease-associated PTMs suppress compensatory responses to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

scholarly journals Exploring Aβ Proteotoxicity and Therapeutic Candidates Using Drosophila melanogaster

2021 ◽  
Vol 22 (19) ◽  
pp. 10448
Author(s):  
Greta Elovsson ◽  
Liza Bergkvist ◽  
Ann-Christin Brorsson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Model Organism ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Disease Genes ◽  
Amyloid Β Peptide ◽  
Drug Candidates ◽  
Human Disease Genes

Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments.

scholarly journals Ingredients in Zijuan Pu’er Tea Extract Alleviate β-Amyloid Peptide Toxicity in a Caenorhabditis elegans Model of Alzheimer’s Disease Likely through DAF-16

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 729 ◽  
Author(s):  
Fangzhou Du ◽  
Lin Zhou ◽  
Yan Jiao ◽  
Shuju Bai ◽  
Lu Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Protective Effect ◽  
Nuclear Translocation ◽  
Amyloid Β ◽  
Amyloid Peptide ◽  
C Elegans ◽  
Β Amyloid

Amyloid-β, one of the hallmarks of Alzheimer’s disease (AD), is toxic to neurons and can also cause brain cell death. Oxidative stress is known to play an important role in AD, and there is strong evidence that oxidative stress is associated with amyloid-β. In the present study we report the protective effect of Zijuan Pu’er tea water extract (ZTWE) and the mixture of main ingredients (+)-catechins, caffeine and procyanidin (MCCP) in ZTWE on β-amyloid-induced toxicity in transgenic Caenorhabditis elegans (C. elegans) CL4176 expressing the human Aβ1–42 gene. ZTWE, (+)-catechins, caffeine, procyanidin and MCCP delayed the β-amyloid-induced paralysis to different degrees. The MCCP treatment did not affect the transcript abundance of amyloid-β transgene (amy-1); however, Thioflavin T staining showed a significant decrease in Aβ accumulation compared to untreated worms. Further research using transgenic worms found that MCCP promoted the translocation of DAF-16 from cytoplasm to nucleus and increased the expression of superoxide dismutase 3 (SOD-3). In addition, MCCP decreased the reactive oxygen species (ROS) content and increased the SOD activity in CL4176 worms. In conclusion, the results suggested that MCCP had a significant protective effect on β-amyloid-induced toxicity in C. elegans by reducing β-amyloid aggregation and inducing DAF-16 nuclear translocation that could activate the downstream signal pathway and enhance resistance to oxidative stress.

scholarly journals Imbalances in Copper or Zinc Concentrations Trigger Further Trace Metal Dyshomeostasis in Amyloid-Beta Producing Caenorhabditis elegans

2021 ◽  
Vol 15 ◽  
Author(s):  
Ada Metaxas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Trace Metals ◽  
Trace Metal ◽  
Amyloid Beta ◽  
Model Organism ◽  
Return To Equilibrium ◽  
C Elegans ◽  
Copper And Zinc ◽  
The Impact

Alzheimer's Disease (AD), a progressive neurodegenerative disease characterized by the buildup of amyloid-beta (Aβ) plaques, is believed to be a disease of trace metal dyshomeostasis. Amyloid-beta is known to bind with high affinity to trace metals copper and zinc. This binding is believed to cause a conformational change in Aβ, transforming Aβ into a configuration more amenable to forming aggregations. Currently, the impact of Aβ-trace metal binding on trace metal homeostasis and the role of trace metals copper and zinc as deleterious or beneficial in AD remain elusive. Given that Alzheimer's Disease is the sixth leading cause of adult death in the U.S., elucidating the molecular interactions that characterize Alzheimer's Disease pathogenesis will allow for better treatment options. To that end, the model organism C. elegans is used in this study. C. elegans, a transparent nematode whose connectome has been fully established, is an amenable model to study AD phenomena using a multi-layered, interconnected approach. Aβ-producing and non-Aβ-producing C. elegans were individually supplemented with copper and zinc. On day 6 and day 9 after synchronization, the percent of worms paralyzed, concentration of copper, and concentration of zinc were measured in both groups of worms. This study demonstrates that dyshomeostasis of trace metals copper or zinc triggers further trace metal dyshomeostasis in Aβ-producing worms, while dyshomeostasis of copper or zinc triggers a return to equilibrium in non-Aβ-producing worms. This supports the characterization of Alzheimer's Disease as a disease of trace metal dyshomeostasis.

scholarly journals Transcriptome analysis of a protein-truncating mutation in sortilin-related receptor 1 associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

2020 ◽  
Author(s):  
Karissa Barthelson ◽  
Stephen Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Reverse Genetics ◽  
Late Onset ◽  
Model Organism ◽  
Amyloid Β ◽  
Targeted Mutagenesis ◽  
Receptor Protein ◽  
Truncating Mutation

AbstractThe early cellular stresses which eventually lead to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.

scholarly journals Phenothiazines to Treat Alzheimer’s Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 639-639
Author(s):  
Rachel Litke ◽  
Bik Tzu Huang ◽  
Damian Gonzalez ◽  
Martine Rampanana ◽  
Nicholas Grimaldi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Model Organism ◽  
Neuronal Model ◽  
Human Diseases ◽  
Protective Effects ◽  
C Elegans ◽  
Novel Drugs ◽  
Pumping Rates

Abstract Current treatments of Alzheimer’s Disease (AD) are largely ineffective and do not address underlying pathophysiological processes. The model organism C. elegans has been successfully used to discover compounds to treat human diseases, some now in clinical trials. To develop novel drugs and explore pathways to treat AD, we took on a forward pharmacological approach with a C. elegans model for AD, completed with studies to expand results to lifespan as well as healthspan. We screened 2560 drugs from the Microsource Spectrum library for their ability to delay proteotoxicity (indicated by paralysis) in an Abeta transgenic C. elegans muscle model of AD (CL2006) in liquid medium. Among the most protective drugs were phenothiazines, which are orally active and cross the blood-brain barrier, desirable properties of drugs to treat AD. 80 phenothiazines congeners were further assessed; 60% were protective in CL2006 worms. 9/20 tested phenothiazines increased lifespan in N2 worms and 2/3 phenothiazines tested promoted significantly higher pharyngeal pumping rates compared with control till day 10 of adulthood in N2 worms. 2 of the drugs were protective in the C. elegans neuronal model of AD. This phenotypic screening approach led to the discovery of potential drugs to treat AD. These phenothiazines protect against Abeta toxicity, and assessment of efficacy to protect against other forms of proteotoxicity are ongoing. These studies suggest the utility of C. elegans to discover drugs to treat human diseases. Future studies will assess molecular mechanisms mediating the protective effects of these compounds.

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