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Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons.
J Alzheimers Dis. 2018; 65(1):243-263.JA

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

Authors+Show Affiliations

Department of Neurology, Saarland University, Homburg, Germany. Department of Neurology, First Affiliated Hospital, Soochow University, Suzhou, China. Department of Neurology, Second Affiliated Hospital, Soochow University, Suzhou, China.Department of Neurology, Saarland University, Homburg, Germany. Department of Clinical Laboratory, Tongji Hospital, Tongji University Medical School, Shanghai, China.Department of Neurology, Saarland University, Homburg, Germany.Department of Neurology, Saarland University, Homburg, Germany.Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany.Department of Neurology, Second Affiliated Hospital, Soochow University, Suzhou, China.Department of Neurology, Saarland University, Homburg, Germany.Department of Neurology, Saarland University, Homburg, Germany. Department of Clinical Laboratory, Tongji Hospital, Tongji University Medical School, Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30010136

Citation

Qin, Yiren, et al. "Ginkgo Biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons." Journal of Alzheimer's Disease : JAD, vol. 65, no. 1, 2018, pp. 243-263.
Qin Y, Zhang Y, Tomic I, et al. Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. J Alzheimers Dis. 2018;65(1):243-263.
Qin, Y., Zhang, Y., Tomic, I., Hao, W., Menger, M. D., Liu, C., Fassbender, K., & Liu, Y. (2018). Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. Journal of Alzheimer's Disease : JAD, 65(1), 243-263. https://doi.org/10.3233/JAD-180426
Qin Y, et al. Ginkgo Biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. J Alzheimers Dis. 2018;65(1):243-263. PubMed PMID: 30010136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. AU - Qin,Yiren, AU - Zhang,Yu, AU - Tomic,Inge, AU - Hao,Wenlin, AU - Menger,Michael D, AU - Liu,Chunfeng, AU - Fassbender,Klaus, AU - Liu,Yang, PY - 2018/7/17/pubmed PY - 2019/7/30/medline PY - 2018/7/17/entrez KW - Alzheimer’s disease KW - Ginkgo biloba extract KW - autophagy KW - inflammation KW - tauopathies SP - 243 EP - 263 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 65 IS - 1 N2 - Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/30010136/Ginkgo_biloba_Extract_EGb_761_and_Its_Specific_Components_Elicit_Protective_Protein_Clearance_Through_the_Autophagy_Lysosomal_Pathway_in_Tau_Transgenic_Mice_and_Cultured_Neurons_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-180426 DB - PRIME DP - Unbound Medicine ER -