Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Ran, Hao; Sun, Lei; Shiu, Ren-Huei; Han, Rui; Hsieh, Chien-Ping; Wei, Tzu-Min; Lo, Chung-Chuan; Chang, Hui-Yun; Sang, Tzu-Kang

doi:10.1038/s41598-020-70423-1

Cited by 9 publications

(6 citation statements)

References 72 publications

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“…These results are consistent with the absence of Tau aggregation or cell death in cell lines and drosophila expressing TauΔD421 (refs. [45][46][47][48] ). Mice expressing endogenous Tau non-cleavable at D421 unexpectedly show Tau hyperphosphorylation, memory impairment, and synaptic plasticity deficits, indicating that TauΔD421 could be beneficial in this model or that the D421N mutation altered Tau function 32 .…”

Section: Discussionmentioning

confidence: 99%

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

2021

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Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2–25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3–25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3–25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

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Section: Discussionmentioning

confidence: 99%

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

2021

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“…Therefore, based on the previous researches (Chi et al 2020;Han et al 2024Han et al , 2021a, we designed behavioral measurement and analysis methods to quantify indices of locomotion. We rst recorded the activity of virgin male and female ies in test tubes over a day using our custom-developed system and employed a Python 3.5 script to capture the position of fruit ies in every frame of the video.…”

Section: Discussionmentioning

confidence: 99%

The impact of different mating systems on locomotion in Drosophila melanogaster

Han,

Zhang,

Wang

et al. 2024

Preprint

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The impact of mating systems on individual behavior and physiology is a significant topic within evolutionary biology and behavioral ecology. This study aims to explore the effects of different mating systems on locomotion in Drosophila melanogaster. By employing various mating contexts such as virginity, monogamy, polygamy, and serial monogamy, the study measures the locomotion of both male and female fruit flies. Results indicate that virgin males exhibit higher locomotion levels including activity level and moving average speed, whereas males in serial monogamy show a notable decrease in activity. In contrast, female locomotion does not significantly differ across mating systems. These findings highlight the influence of mating behaviors on male physiological states and suggest potential implications for lifespan related to mating strategies. This research provides novel insights into the impact of mating strategies on the behavioral and physiological mechanisms in animals, and establishes a fundamental understanding of the application of Drosophila melanogaster as a model organism in the study of behavioral biology.

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“…More recently, a study demonstrated that in mice, blocking Tau cleavage by caspase-3 resulted in memory deficits ( Biundo et al, 2017 ). In Drosophila , caspase 3 cleavage of hyperphosphorylated Tau prevented its toxicity and allowed recovery of motor deficits ( Chi et al, 2020 ). From these results, it appears that the increased cleavage of Tau by caspase-3 upon VAMP8 overexpression could be neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

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In Alzheimer’s disease, Tau, a microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, and accumulates in the somato-dendritic compartment where it forms insoluble aggregates. Tau also accumulates in the CSF of patients indicating that it is released by neurons. Consistent with this, several laboratories including ours have shown that Tau is secreted by neurons through unconventional secretory pathways. Recently, we reported that VAMP8, an R-SNARE found on late endosomes, increased Tau secretion and that secreted Tau was cleaved at the C-terminal. In the present study, we examined whether the increase of Tau secretion by VAMP8 affected its intra- and extracellular cleavage. Upon VAMP8 overexpression, an increase of Tau cleaved by caspase-3 in the cell lysate and medium was observed. This was correlated to an increase of active caspase-3 in the cell lysate and medium. Using a Tau mutant not cleavable by caspase-3, we demonstrated that Tau cleavage by caspase-3 was not necessary for its secretion upon VAMP8 overexpression. By adding recombinant Tau to the culture medium, we demonstrated that extracellular Tau cleavage by caspase-3 could occur because of the release of active caspase-3, which was the highest when VAMP8 was overexpressed. When cleavage of Tau by caspase-3 was prevented by using a non-cleavable mutant, secreted Tau was still cleaved at the C-terminal, the asparagine N410 contributing to it. Lastly, we demonstrated that N-terminal of Tau regulated the secretion pattern of a Tau fragment containing the microtubule-binding domain and the C-terminal of Tau upon VAMP8 overexpression. Collectively, the above observations indicate that VAMP8 overexpression affects the intra- and extracellular cleavage pattern of Tau.

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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Cited by 9 publications

References 72 publications

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

The impact of different mating systems on locomotion in Drosophila melanogaster

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

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