Elsevier

Neuroscience Letters

Volume 720, 16 February 2020, 134749
Neuroscience Letters

Research article
Geniposide effectively reverses cognitive impairment and inhibits pathological cerebral damage by regulating the mTOR Signal pathway in APP∕PS1 mice

https://doi.org/10.1016/j.neulet.2020.134749Get rights and content

Highlights

  • PI3-K/Akt/mTOR signaling pathway performs the effect of longevity and health span as a nutrient and growth factor sensing and inhibition of the mTOR had being developed into a novel for AD therapy.

  • Geniposide reverse AD pathophysiological process as a glucagon-like-1 receptor agonist.

  • Geniposide protect against AD by inhibiting PI3-K/Akt/mTOR signaling pathway and enhancing autophagy.

Abstract

Objective

The aim of this study is to investigate the protective effects as well as the underlying molecular mechanisms of geniposide in APP/PS1 transgenic mice.

Method

APP/PS1 mice were subjected to intragastric administration of geniposide (50 mg/kg/d) for 8 weeks (including a 2-week behavior test). The novel object recognition (NOR) and the Morris water maze (MWM) tests were used for behavioral assessments. Aβ1-40 plaques in mice cortices and hippocampi are visualized with immunohistochemistical staining. ELISA was used to quantify the levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus. Western blot was used to detect p-Akt/Akt, p-mTOR/mTOR and p-4E-BP1/4E-BP1 levels. The relative mRNA levels of Akt, mTOR and 4E-BP1 were quantified using real-time PCR (RT-PCR).

Results

Geniposide alleviated cognitive impairment by improving the ability of novel object exploration, spatial memory, and reduced the level of Aβ in the brain of APP/PS1 mice. Geniposide possibly regulates mTOR-related proteins through modification of phosphorylation. Geniposide markedly lowered p-mTOR and p-Akt expressions while elevating p-4E-BP1 expression. Geniposide obviously reduced the relative mRNA levels of Akt and mTOR and increased the relative mRNA level of 4E-BP1.

Conclusion

Geniposide is able to alleviate cognitive impairments and cerebral damage in APP/PS1 mice, with its neuroprotective effects likely mediated via modulation of the mTOR signaling pathway.

Introduction

The Chinese herb Gardenia is commonly utilized for treating inflammatory, cerebral and hepatic disorders [1,2]. Geniposide is the primary active compound extracted from the Gardenia jasminoidesellis fruit. Liu et al. [3] has previously isolated geniposide as a GLP-1 receptor agonist via high-throughput screening methods. Geniposide was also demonstrated to work in a GLP-1 dependent mechanism [4]. Geniposide has been proven to be able to easily cross the blood-brain barrier [5], leading to several studies focused on exploring its utility in treating neurodegenerative diseases [6]. Geniposide has been shown to reverse memory impairment and τ phosphorylation in streptozotocin (STZ)-injected rats [6]. However, the mechanisms underlying these effects have yet to be fully clarified.

The risk of AD increases significantly with age. The process of aging results in the accumulation of several damaging effects in cells that culminates in disease and death [11,12]. Rapamycin (mTOR), a serine/threonine protein kiniase, is responsible for regulating cellular growth as well as cellular homeostasis. The mTOR signaling pathway plays a significant role in aging, lifespan and aged-related diseases including diabetes and AD [13]. Huang et al. [14] showed that geniposide was able to protect neurons against post-ischemic neurovascular injury through the mTOR pathway, highlighting the potential benefits of GLP-1 therapy in neurodegenerative diseases. Additionally, Yin et al. [15] put forward that phosphatidylinositol 3-kinase (PI3K)/Akt activation may also be essential in mediating geniposide’s protective effects.

We hypothesize that the mTOR pathway is central in facilitating geniposide-mediated neuroprotection. In the present study, we attempt to verify this hypothesis by assessing behavioral changes as well as quantifying Aβ expressions and the proteins related to mTOR signaling pathway after geniposide treatment in APP/PS1 mice.

Section snippets

Chemicals

Geniposide (purity> 98%) was bought from Med Che Express. All antibodies including anti-Aβ1-40, anti-p-Akt, anti-Akt, anti-p-mTOR, anti-mTOR,anti-p-4E-BP1, andanti-4E-BP1were obtained from Abcam Technology Inc. RIPA lysis buffer was obtained from Beyotime Institute of Biotechnology.4% Paraformaldehyde, ELISA kits for Aβ1-40 and Aβ1-42 as well as cDNA Synthesis kit were procured from Boster Biotechnology Co., Ltd.

Animals and drug administration

APP/PS1 double-transgenic mice and C57BL background mice (6 months, male) were

Geniposide improved the ability of APP/PS1 mice to identify new objects

The NOR test was used to estimate the intelligence of mice. The recognition index (RI)for A1 or A2 is calculated as the ratio of time taken to explore either A1 or A2 (TA1 or TA2) to the time taken to explore both A1 and A2(TA1 + TA2)[RI = TA1 or TA2/(TA1 + TA2)]. RI of mice in each group was compared. There was no significant difference in RI for A1 and A2 across all three groups (Fig. 2A).

RI for new objects was taken as the ratio of the time used to explore a new object (B) (TN) to the total

Discussion

Our previous study verified that geniposide revised memory impairments and τ phosphorylation in streptozotocin (STZ)-induced rat models of AD [6]. Our current investigations further demonstrates that geniposide treatment can improve the ability of new object identification, ameliorate learning and memory impairments as well as reduce Aβ1-40plaques in cortex and hippocampus along with soluble Aβ1-40 and Aβ1-42 in hippocampus of APP/PS1 mice through inhibition the mTOR signaling pathway.

In the

Conclusion

In conclusion, our results suggest that geniposide significantly inhibits the mTOR signaling pathway in APP/PS1 mice. This signaling pathway may be responsible in allowing geniposide to confer its beneficial effects in AD.

Ethics approval and consent to participate

This study was approved by the Shanxi Medical University ethic committee and consent to participate was provided by all participants.

Author contributions

Zhang Zhihua, Gao Wenping and Wang Xiaojian were involved in the design and execution of the study. They contributed to the development of the manuscript and reviewed and approved the final version of the manuscript. Zhang Di directed the statistical analysis of the data, contributed to the development of the manuscript, and reviewed and approved the final version of the manuscript. Yueze Liu and Li Lin were involved in the design and execution of the study, contributed to the development of

Consent for publication

Not applicable

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Funding

Research project was supported by Shanxi Scholarship Council of China (2017- important 4), and by the Fund for Shanxi “1331 Project” Key Subjects Construction.

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgements

I am grateful to Professor jinshun Qi (employees of Shanxi Medical University) and Doctor yanwei Li (employees of Shaoyang medical college) who provided me a lot of assistance in the process of experiment implementation.

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