Generation and characterization of a tractable C. elegans model of tauopathy

Russell, Joshua; Lei, Haoyi; Chaliparambil, Rahul K; Fish, Sarah; Markiewicz, Susan M; Lee, Ting-I; Noori, Anushka; Kaeberlein, Matt

doi:10.1007/s11357-021-00436-9

Cited by 3 publications

(8 citation statements)

References 69 publications

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“…These defects are suppressed by RNAi directed against tau mRNA. This model could be a useful tool for applying RNAi screening to the study of mechanisms influencing human tau hyperphosphorylation and toxicity [ 121 ].…”

Section: C Elegans Models To Study the Function And Mechanis...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: C Elegans Models To Study the Function And Mechanis...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…Because we previously noted a general improvement in health with age in animals treated OFs, we next characterized the effects of OFs in detail in both WT and hTau-expressing animals. Previous studies have documented the negative effects of tau proteotoxicity on multiple fitness parameters, developmental growth, and timing and brood size [4]. OFA and OFB treatment were both capable of significantly reversing the impaired reproductive output of hTau-expressing worms ( Figure 3A-B ), specifically towards the end of the reproductive span at days 3-5 of adulthood (Figure S3A).…”

Section: Resultsmentioning

confidence: 71%

“…We next measured the impact of OFA and OFB treatment on the decline in muscle function resulting from hTau-expression [4]. We confirmed the impaired crawling and thrashing speed in hTau-expressing animals and noted a significant improvement of both movement parameters with treatment of either OFA or OFB at Day 2 and Day 4 of adulthood.…”

Section: Resultsmentioning

confidence: 74%

“…In early stages of Alzheimer’s disease, tau becomes hyperphosphorylated and mislocalized, which can contribute to its aggregation and toxicity [15, 16]; and this hyperphosphorylation is mimicked in the C. elegans hTau-expressing model [4]. To measure the impact of OFs treatment on tau protein dynamics we examined the phosphorylation status ( Figure 2A-C ) and aggregation propensity (Figure S2A) of the hTau protein in the hTau-expressing animals treated with OFA and OFB as compared to mock-treated controls.…”

Section: Resultsmentioning

confidence: 99%

“…Our results demonstrate that OFs can reverse tau aggregation in C. elegans and lysates from human AD brains, but also promote health improvements in the C. elegans tauopathy model. C. elegans worms which expressed human tau exhibit a shortened lifespan, due to tau-induced proteotoxicity, proteostasis loss, apoptosis and eventually cause death [3, 4, 23]. Similar to the lifespan-promoting effects of OFs on WT animals, OFs treatment can also increase the lifespan of the short-lived tau-expressing C. elegans model of tauopathy.…”

Section: Discussionmentioning

confidence: 99%

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Oolonghomobisflavans fromCamellia sinensisdisaggregate tau fibrils across Alzheimer’s disease models

Duangjan,

Chang,

Seidler

et al. 2024

Preprint

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Alzheimer's disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-beta (AB) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in a C. elegans model expressing pathogenic human tau ("hTau-expressing") and promoted Tau disaggregation and inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer's disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressing C. elegans model, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.

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Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models

Ganguly,

Carroll,

Nehrke

et al. 2024

Antioxidants

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

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Generation and characterization of a tractable C. elegans model of tauopathy

Cited by 3 publications

References 69 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Oolonghomobisflavans fromCamellia sinensisdisaggregate tau fibrils across Alzheimer’s disease models

Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models

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