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BHBA Treatment Improves Cognitive Function by Targeting Pleiotropic Mechanisms in a Transgenic Mouse Model of Alzheimer's Disease

54 Pages Posted: 19 Jul 2019

See all articles by Yancheng Wu

Yancheng Wu

Zhongkai University of Agriculture and Engineering - College of Animal Science & Technology

Yuhong Gong

Jilin University (JLU) - College of Veterinary Medicine

Yongxin Luan

Jilin University (JLU)

Yang Li

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

Juxiong Liu

Jilin University (JLU) - Department of Theoretic Veterinary Medicine

Zitong Yue

Changchun Jida Middle School Experimental School

Boyu Yuan

Jilin University (JLU) - College of Veterinary Medicine

Jingxuan Sun

Jilin University (JLU) - College of Veterinary Medicine

Changxin Xie

Jilin University (JLU) - College of Veterinary Medicine

Lijuan Li

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

Junli Zhen

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

Xinxin Jin

Jilin University (JLU) - College of Veterinary Medicine

Yan Zheng

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

Xiaomin Wang

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

Liwei Xie

State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, G

Wei Wang

Jilin University (JLU) - College of Veterinary Medicine; Zhongkai University of Agriculture and Engineering - College of Animal Science & Technology; Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

More...

Abstract

Background: Accumulation of amyloid β (Aβ) peptide, inflammation, and oxidative stress contribute to Alzheimer's disease (AD) and trigger complex pathogenesis. The ketone body β-hydroxybutyrate (BHBA) is an endogenous metabolic intermediate that protects against stroke and neurodegenerative diseases, but the underlying mechanisms are unclear. The present study aims to elucidate the protective effects of BHBA in the early stage of AD model and investigate the underlying molecular mechanisms.

Methods: 3.5-month old double-transgenic mice (5XFAD) overexpressing β-amyloid precursor protein (APP) and presenilin-1 (PS1) were used as the AD model. The 5XFAD mice received 1.5 mmol/kg/d BHBA subcutaneously for 28 days. Morris water maze test, nest construction, and passive avoidance experiments were performed to assess the therapeutic effects on AD prevention in vivo, and brain pathology of 5XFAD mice including amyloid plaque deposition and microglia activation were assessed. Gene expression profiles in the cortexes of 5XFAD and BHBA-treated 5XFAD mice were performed with high-throughput sequencing and bioinformatic analysis. Mouse HT22 cells were treated with 2 mM BHBA to explore its in vitro protective effects of BHBA on hippocampal neurons against Aβ oligomer toxicity, ATP production, ROS generation, and mitochondrial aerobic respiratory function. APP, BACE1, and neprilysin (NEP) expression levels were evaluated in HT22 cells following treatment with BHBA by measuring the presence or absence of G protein-coupled receptor 109A(GPR109A).

Findings: BHBA improved cognitive function of 5XFAD mice in Morris water maze test, nesting construction, and passive avoidance experiments, and attenuated Aβ accumulation and microglia overactivation in the brain. BHBA also enhanced mitochondrial respiratory function and histone butyrylation of hippocampal neurons and protected them from Aβ toxicity. The enzymes, APP and NEP were regulated by BHBA via G protein-coupled receptor 109A (GPR109A). Furthermore, RNA sequencing revealed that BHBA regulated genes mainly annotated in aging, immune system, nervous system, and neurodegenerative diseases.

Interpretation: Our data suggested that BHBA confers protection against the AD-like pathological events in the AD mouse model by targeting multiple aspects of AD and it may become a promising candidate for the prevention and treatment of AD.

Funding Statement: This work was funded by the National Nature Science Foundation of China (31572479, 31872442) and Program for JLU Science and Technology Innovative Research Team (2017TD-30).

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: All animal experiments in this study have been approved by the Jilin University Institutional Animal Care and Use Committee (Permit number: 201704005).

Keywords: Alzheimer's disease, β-Amyloid, Microglia, Inflammation, BHBA, 5XFAD mice

Suggested Citation

Wu, Yancheng and Gong, Yuhong and Luan, Yongxin and Li, Yang and Liu, Juxiong and Yue, Zitong and Yuan, Boyu and Sun, Jingxuan and Xie, Changxin and Li, Lijuan and Zhen, Junli and Jin, Xinxin and Zheng, Yan and Wang, Xiaomin and Xie, Liwei and Wang, Wei and Wang, Wei, BHBA Treatment Improves Cognitive Function by Targeting Pleiotropic Mechanisms in a Transgenic Mouse Model of Alzheimer's Disease (July 15, 2019). Available at SSRN: https://ssrn.com/abstract=3421582 or http://dx.doi.org/10.2139/ssrn.3421582

Yancheng Wu

Zhongkai University of Agriculture and Engineering - College of Animal Science & Technology

China

Yuhong Gong

Jilin University (JLU) - College of Veterinary Medicine

China

Yongxin Luan

Jilin University (JLU)

Guilin Road
Chaoyang, Changchun 130021
China

Yang Li

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

China

Juxiong Liu

Jilin University (JLU) - Department of Theoretic Veterinary Medicine ( email )

Zitong Yue

Changchun Jida Middle School Experimental School

China

Boyu Yuan

Jilin University (JLU) - College of Veterinary Medicine

China

Jingxuan Sun

Jilin University (JLU) - College of Veterinary Medicine

China

Changxin Xie

Jilin University (JLU) - College of Veterinary Medicine

China

Lijuan Li

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

China

Junli Zhen

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

China

Xinxin Jin

Jilin University (JLU) - College of Veterinary Medicine

China

Yan Zheng

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education ( email )

China

Xiaomin Wang

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education

China

Liwei Xie

State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, G ( email )

Guangzhou, 510070
China

Wei Wang (Contact Author)

Jilin University (JLU) - College of Veterinary Medicine ( email )

Guilin Road
Chaoyang
Changchun, Jilin 130021
China

Zhongkai University of Agriculture and Engineering - College of Animal Science & Technology ( email )

China

Capital Medical University - Key Laboratory for Neurodegenerative Disorders of the Ministry of Education ( email )

China

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