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Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies

BACKGROUND: Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology...

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Autores principales: Tong, Benjamin Chun-Kit, Huang, Alexis Shiying, Wu, Aston Jiaxi, Iyaswamy, Ashok, Ho, Olivia Ka-Yi, Kong, Anna Hau-Yee, Sreenivasmurthy, Sravan Gopalkrishnashetty, Zhu, Zhou, Su, Chengfu, Liu, Jia, Song, Juxian, Li, Min, Cheung, King-Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587578/
https://www.ncbi.nlm.nih.gov/pubmed/36273169
http://dx.doi.org/10.1186/s12929-022-00871-6
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author Tong, Benjamin Chun-Kit
Huang, Alexis Shiying
Wu, Aston Jiaxi
Iyaswamy, Ashok
Ho, Olivia Ka-Yi
Kong, Anna Hau-Yee
Sreenivasmurthy, Sravan Gopalkrishnashetty
Zhu, Zhou
Su, Chengfu
Liu, Jia
Song, Juxian
Li, Min
Cheung, King-Ho
author_facet Tong, Benjamin Chun-Kit
Huang, Alexis Shiying
Wu, Aston Jiaxi
Iyaswamy, Ashok
Ho, Olivia Ka-Yi
Kong, Anna Hau-Yee
Sreenivasmurthy, Sravan Gopalkrishnashetty
Zhu, Zhou
Su, Chengfu
Liu, Jia
Song, Juxian
Li, Min
Cheung, King-Ho
author_sort Tong, Benjamin Chun-Kit
collection PubMed
description BACKGROUND: Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. METHODS: Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca(2+)) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca(2+) and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo. RESULTS: We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca(2+) release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia. CONCLUSIONS: Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca(2+) homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00871-6.
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spelling pubmed-95875782022-10-23 Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies Tong, Benjamin Chun-Kit Huang, Alexis Shiying Wu, Aston Jiaxi Iyaswamy, Ashok Ho, Olivia Ka-Yi Kong, Anna Hau-Yee Sreenivasmurthy, Sravan Gopalkrishnashetty Zhu, Zhou Su, Chengfu Liu, Jia Song, Juxian Li, Min Cheung, King-Ho J Biomed Sci Research BACKGROUND: Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. METHODS: Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca(2+)) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca(2+) and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo. RESULTS: We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca(2+) release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia. CONCLUSIONS: Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca(2+) homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00871-6. BioMed Central 2022-10-22 /pmc/articles/PMC9587578/ /pubmed/36273169 http://dx.doi.org/10.1186/s12929-022-00871-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Tong, Benjamin Chun-Kit
Huang, Alexis Shiying
Wu, Aston Jiaxi
Iyaswamy, Ashok
Ho, Olivia Ka-Yi
Kong, Anna Hau-Yee
Sreenivasmurthy, Sravan Gopalkrishnashetty
Zhu, Zhou
Su, Chengfu
Liu, Jia
Song, Juxian
Li, Min
Cheung, King-Ho
Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title_full Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title_fullStr Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title_full_unstemmed Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title_short Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
title_sort tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587578/
https://www.ncbi.nlm.nih.gov/pubmed/36273169
http://dx.doi.org/10.1186/s12929-022-00871-6
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