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Protective effect of potassium 2-(l-hydroxypentyl)-benzoate on hippocampal neurons, synapses and dystrophic axons in APP/PS1 mice

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Abstract

Rationale

As the hub of memory and space, hippocampus is very sensitive to a wide variety of injuries and is one of the earliest brain structures to develop neurodegenerative changes in AD. Previous research has showed a protective effect of potassium 2-(l-hydroxypentyl)-benzoate (PHPB) on cognitive deficits in animal models of AD. However, it is unclear whether this protective effect is associated with hippocampal alterations.

Objectives

The present study was conducted to evaluate the protective effect of PHPB on hippocampal neurodegenerative changes in middle-aged APP/PS1 mice.

Methods

Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups. PHPB-treated APP/PS1 group received 30 mg/kg PHPB by oral gavage once daily for 12 weeks. Wild-type group and APP/PS1 group received the same volume of water alone. Twelve weeks later, mice (13-month-old) were tested for in vivo 1H-MRS examination and then sacrificed for subsequent biochemical and pathological examinations using transmission electron microscopy, Golgi staining, immunohistochemistry, and western blotting.

Results

We found that PHPB treatment significantly improved the micromorphology of hippocampal neurons and subcellular organelles, ameliorated synapse loss and presynaptic axonal dystrophy, increased hippocampal dendritic spine density and dendritic complexity, enhanced the expression of hippocampal synapse-associated proteins, and improved hippocampal metabolism in middle-aged APP/PS1 mice.

Conclusions

Our study showed for the first time the protective effect of PHPB on hippocampal neurons, synapses, and dystrophic axons in APP/PS1 mice, which to some extent revealed the possible mechanism for its ability to improve cognition in animal models of AD.

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Funding

This project was supported by the grants from National Natural Sciences Foundation of China (No.81473200 and 81673420), CAMS Innovation Fund for Medical Sciences (No.2017-I2M-2-004), and the National Science and Technology Major Special Project on Major New Drug Innovation of China (2018ZX09711001-003-005, 2018ZX09711001-003-009).

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Longjian Huang, Yong Zhang, Yuchen Peng, Yujun Zhou, Xiaoliang Wang & Ying Peng

  2. Trinity College of Arts and Sciences, Duke University, Durham, NC, 27708, USA

    Zirun Zhao

  3. Pharmacology Department, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Xiannongtan Street, Xicheng District, Beijing, 100050, China

    Xiaoliang Wang & Ying Peng

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  1. Longjian Huang
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  2. Yong Zhang
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  3. Yuchen Peng
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  4. Zirun Zhao
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  5. Yujun Zhou
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  6. Xiaoliang Wang
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  7. Ying Peng
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Corresponding authors

Correspondence to Xiaoliang Wang or Ying Peng.

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All experiments were approved and performed in accordance with the institutional guidelines of the Experimental Animal Center of the Chinese Academy of Medical Science, Beijing, China (No.00005668).

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Huang, L., Zhang, Y., Peng, Y. et al. Protective effect of potassium 2-(l-hydroxypentyl)-benzoate on hippocampal neurons, synapses and dystrophic axons in APP/PS1 mice. Psychopharmacology 236, 2761–2771 (2019). https://doi.org/10.1007/s00213-019-05251-x

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