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Activation of the TREK-1 Potassium Channel Improved Cognitive Deficits in a Mouse Model of Alzheimer’s Disease by Modulating Glutamate Metabolism

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction. The glutamate (Glu) metabolic pathway may be a major contributor to the memory dysfunction associated with AD. The TWIK-related potassium channel-1 (TREK-1) protects against brain ischemia, but any specific role for the channel in AD remains unknown. In this study, we used SAMP8 mice as an AD model and age-matched SAMR1 mice as controls. We explored the trends of changes in TREK-1 channel activity and the levels of AD-related molecules in the brains of SAMP8 mice. We found that the expression level of TREK-1 increased before 3 months of age and then began to decline. The levels of Tau and Glu increased with age whereas the acetylcholine level decreased with age. α-Linolenic acid (ALA), an activator of the TREK-1 channel, significantly increased the TREK-1 level, and improved the learning and memory deficits of SAMP8 mice aged 6 months. The mechanism in play may involve the Glu metabolic pathway. After activation of the TREK-1 channel, damaged neurons and astrocytes were rescued, the levels of Glu and the N-methyl-D-aspartate receptor were downregulated, and the level of glutamate transporter-1 was upregulated. These findings suggest that TREK-1 plays a crucial role in the pathological progression of AD; activation of the TREK-1 channel improved cognitive deficits in SAMP8 mice via a mechanism that involved Glu metabolism. The TREK-1 potassium channel may thus be a valuable therapeutic target in AD patients.

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Data Availability

Data supporting the results of this study are available upon reasonable request of the corresponding author.

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Acknowledgements

We thank the members of the Lu Li Laboratory, Institute of Pharmacology, Lanzhou University School of Basic Medicine, for their constructive feedback on the production of this manuscript.

Funding

This study was supported by the Key Laboratory of Traditional Chinese Medicine Innovation and Transformation of Gansu Province/Engineering Laboratory of Traditional Chinese Medicine Products of Gansu Province (ZYFYZH-KJ-2016–004) and the Talent Innovation and Entrepreneurial Science and Technology Project of Lanzhou City (2015-RC-20).

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Authors and Affiliations

  1. School of Basic Medical Sciences, Lanzhou University, Lanzhou, 73000, Gansu, China

    Fang Li, Shu-ning Zhou, Xin Zeng, Zhen Li, Xue-xi Wang & Li Lu

  2. The College of Traditional Chinese Medicine, Zhejiang Pharmaceutical College, Ningbo, 315000, Zhejiang, China

    Shu-ning Zhou

  3. The Endocrinology Department, Lanzhou Hospital of Traditional Chinese Medicine, Lanzhou, 73000, Gansu, China

    Rui Yang

  4. The Second Clinical Medical College, Lanzhou University, Lanzhou, 73000, Gansu, China

    Bin Meng & Wei-lin Pei

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  1. Fang Li
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  3. Xin Zeng
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Contributions

F Li has full access to all data in the study and is responsible for the integrity of the data and the accuracy of the data analysis. SN Zhou and F Li contributed equally to this work and are co-first authors. F Li collected the data and drafted and revised the manuscript. SN Zhou analyzed the data. X Zeng did animal experiments, Z Li finished ELISA detection, and R Yang and XX Wang contributed to section staining. B Meng and WL Pei collected the data. L Li designed the study and F Li interpreted data and reviewed the manuscript. L Li and XX Wang did critical revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rui Yang or Li Lu.

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All the animal experiments were conducted according to the guidelines for animal care and use in China. The authors also confirm that the study was performed in accordance with the approval of the ethical committee for animal experimentation at Lanzhou University.

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Fang Li and Shu-ning Zhou are co-first authors.

Li Lu is the first corresponding author and Rui Yang is the second corresponding author.

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Li, F., Zhou, Sn., Zeng, X. et al. Activation of the TREK-1 Potassium Channel Improved Cognitive Deficits in a Mouse Model of Alzheimer’s Disease by Modulating Glutamate Metabolism. Mol Neurobiol 59, 5193–5206 (2022). https://doi.org/10.1007/s12035-022-02776-9

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