期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 65, 期 1, 页码 243-263出版社
IOS PRESS
DOI: 10.3233/JAD-180426
关键词
Alzheimer's disease; autophagy; Ginkgo biloba extract; inflammation; tauopathies
资金
- Else Kroner-Fresenius Foundation [2012_A247]
- National Natural Science Foundation of China [81701051]
- Dr. Willmar Schwabe GmbH Co. KG
Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid beta (A beta) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). A beta and p-Tau are two major pathogenic molecules with tau acting downstream to A beta 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-3 beta. 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.
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