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Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

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Abbreviations

AD :

Alzheimer’s disease

Aβ :

amyloid-beta

ThT :

Thioflavin T

DMEM :

Dulbeco’s modified Eagle’s medium

FBS :

fetal bovine serum

CCK :

cell counting kit

MAP-2 :

microtubule-associated protein-2

CDK5 :

cyclin-dependent kinase 5

GSK-3β :

glycogen synthase kinase-3β

LC 3 :

microtubule-associated protein II light chain 3

SIRT1 :

silent information regulator of transcription 1

LKB1 :

liver kinase B1

AMPK :

adenosine monophosphate-activated protein kinase

mTOR :

mechanistic target of rapamycin

p70S6K :

p70 ribosomal protein S6 kinase

APP :

amyloid precursor protein

PERK :

protein kinase RNA-like endoplasmic reticulum kinase

eIF2α :

eukaryotic translation initiation factor-2α

BACE1 :

β-secretase 1

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Acknowledgements

The authors thank the Instrumental Analysis Center of Shenzhen University (Xili Campus) for their assistance in our experiments.

Availability of Data and Material

All data is real and guarantees the validity of experimental results.

Funding

This work was supported financially by National Natural Science Foundation of China (31871734), National Key R&D Program of China (2018YFD0901106), National Natural Science Foundation of China (31970366), Guangdong Natural Science Foundation (2018A0303130054 and 2018A030313507), the Science and Technology Innovation Commission of Shenzhen (JCYJ20190808141415052, JCYJ20180507182405562, JCYJ20180305124211995 and JCYJ20180305125619343), National Key Project for Synthetic Biology (SQ2018YFA090029).

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  1. Meiting Li and Nan Cai contributed equally to this work.

Authors and Affiliations

  1. Shenzhen Key Laboratory of Marine Bioresources and Ecology, Guangdong Provincial Key Laboratory for Plant Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, People’s Republic of China

    Meiting Li, Nan Cai, Liang Gu, Lijun Yao, Decheng Bi, Hong Xu, Hui Li, Zhangli Hu & Xu Xu

  2. Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China

    Nan Cai & Liang Gu

  3. School of Medicine, Shenzhen University, Shenzhen, 518055, People’s Republic of China

    Weishan Fang

  4. Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China

    Zhijian Lin

  5. Instrumental Analysis Center, Shenzhen University, Shenzhen, 518055, People’s Republic of China

    Yan Wu

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  1. Meiting Li
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Contributions

Meiting Li, Nan Cai, Liang Gu, Hui Li, and Zhangli Hu conceived and designed the project. Meiting Li, Nan Cai, Liang Gu, Lijun Yao, and Decheng Bi performed majority of the experiments. Meiting Li, Nan Cai, Weishan Fang, Zhijian Lin, and Hong Xu performed data analyzes. Meiting Li, Nan Cai, Xu Xu, Weishan Fang, Zhijian Lin, Hong Xu, Hui Li, and Zhangli Hu wrote the manuscript. Xu Xu, Meiting Li, Nan Cai, and Yan Wu revised the paper. Xu Xu supervised the paper.

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Correspondence to Xu Xu.

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Li, M., Cai, N., Gu, L. et al. Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer’s Disease. Mol Neurobiol 58, 4134–4144 (2021). https://doi.org/10.1007/s12035-021-02389-8

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