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Effects of Involuntary and Voluntary Exercise in Combination with Acousto-Optic Stimulation on Adult Neurogenesis in an Alzheimer's Mouse Model

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Abstract

Single-factor intervention, such as physical exercise and auditory and visual stimulation, plays a positive role on the prevention and treatment of Alzheimer’s disease (AD); however, the therapeutic effects of single-factor intervention are limited. The beneficial effects of these multifactor combinations on AD and its molecular mechanism have yet to be elucidated. Here, we investigated the effect of multifactor intervention, voluntary wheel exercise, and involuntary treadmill running in combination with acousto-optic stimulation, on adult neurogenesis and behavioral phenotypes in a mouse model of AD. We found that 4 weeks of multifactor intervention can significantly increase the production of newborn cells (BrdU+ cells) and immature neurons (DCX+ cells) in the hippocampus and lateral ventricle of Aβ oligomer-induced mice. Importantly, the multifactor intervention could promote BrdU+ cells to differentiate into neurons (BrdU+ DCX+ cells or BrdU+ NeuN+ cells) and astrocytes (BrdU+GFAP+ cells) in the hippocampus and ameliorate Aβ oligomer-induced cognitive impairment and anxiety- and depression-like behaviors in mice evaluated by novel object recognition, Morris water maze tests, elevated zero maze, forced swimming test, and tail suspension test, respectively. Moreover, multifactor intervention could lead to an increase in the protein levels of PSD-95, SYP, DCX, NeuN, GFAP, Bcl-2, BDNF, TrkB, and pSer473-Akt and a decrease in the protein levels of BAX and caspase-9 in the hippocampal lysates of Aβ oligomer-induced mice. Furthermore, sequencing analysis of serum metabolites revealed that aberrantly expressed metabolites modulated by multifactor intervention were highly enriched in the biological process associated with keeping neurons functioning and neurobehavioral function. Additionally, the intervention-mediated serum metabolites mainly participated in glutamate metabolism, glucose metabolism, and the tricarboxylic acid cycle in mice. Our findings suggest the potential of multifactor intervention as a non-invasive therapeutic strategy for AD to anti-Aβ oligomer neurotoxicity.

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Data Availability

The data generated during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-beta

NBM:

Nucleus basalis magnocellularis

PSD-95:

Postsynaptic density 95

SYP:

Synaptophysin

DCX:

Doublecortin

NeuN:

Neuronal nuclei

GFAP:

Glial fibrillary acidic protein

Bcl-2:

B cell chronic lymphoma-2

ICR:

Institute of Cancer Research

NIH:

National Institutes of Health

HFIP:

Hexafluoroisopropanol

LED:

Light-emitting diode

i.p.:

Intraperitoneal

BrdU:

5′-Bromo-2′-deoxyuridine

aNSCs:

Adult neural stem cells

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

DAPI:

4′6-Diamidino-2-phenylindole

MWM:

Morris water maze

NOR:

Novel object recognition

EZM:

Elevated zero maze

FST:

Forced swimming test

TST:

Tail suspension test

PVDF:

Polyvinylidene difluoride membranes

GC-MS:

Gas chromatography-mass spectrometry

EDTA:

Ethylenediaminetetraacetic acid

QC:

Quality control

CAMERA:

Collection of algorithms of metabolite profile annotation

PCA:

Principal component analysis

PLS-DA:

Partial least square discriminant analysis

VIP:

Variable importance in the projection

ANOVA:

Analysis of variance

SGZ:

Subgranular zones

SVZ:

Subventricular zone

DG:

Dentate gyrus

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tropomyosin-related kinase receptor type B

UHPLC-Q-TOF/MS:

Ultra-performance liquid chromatography and quadrupole time-of-flight/metabolomics

OPLS-DA:

Orthogonal partial least-squares discriminant analysis

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Acknowledgements

The authors thank the technical support by the Core Facilities, Ningbo University School of Medicine, and the Laboratory Animal Center, Ningbo University.

Funding

This work was supported by National Natural Science Foundation of China (No. 82001155 and No. 32171035), the Natural Science Foundation of Zhejiang Province (No.LQ19H090005 and No.LQ19H090001), Ningbo Science and Technology Bureau (No.2019B10034), the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2022KY1144 and No.2019RC316), Scientific Research Fund Project of Ningbo University (XYL20030), the Student Research, Innovation Program of Ningbo University (2021SRIP), and the K. C. Wong Magna Fund in Ningbo University.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo, Zhejiang, 315211, People’s Republic of China

    Wan-yi Li, Jun-yan Gao, Su-Yang Lin, Shao-tao Pan, Biao Xiao, Yu-tao Ma, Qin-wen Wang & Li-ping Li

  2. Rehabilitative Department, the Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, 315211, People’s Republic of China

    Wan-yi Li, Kai Xie, Wei Shen & Li-ping Li

  3. Faculty of Sports Science, Ningbo University, Ningbo, 315211, Zhejiang, China

    Wan-yi Li, Zhi-tao Liu & Guang-yu Li

  4. Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, 315211, People’s Republic of China

    Jun-yan Gao, Su-Yang Lin, Shao-tao Pan, Yu-tao Ma & Qin-wen Wang

  5. The First People’s Hospital of Wenling, Taizhou, Zhejiang315211, China

    Jie-jie Guo

  6. Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, Zhejiang, 315010, People’s Republic of China

    Li-ping Li

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  1. Wan-yi Li
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  7. Kai Xie
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  8. Wei Shen
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  11. Jie-jie Guo
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Contributions

Li-ping Li designed the experiments. Wan-yi Li performed the behavioral experiments. Jun-yan Gao and Su-Yang Lin performed the immunohistochemical experiments. Shao-tao Pan, Biao Xiao, Yu-tao Ma, and Zhi-tao Liu performed the biochemical experiments. Kai Xie, Wei Shen, Qin-wen Wang, Guang-yu Li, and Jie-jie Guo carried out the data analysis. Li-ping Li, Wan-yi Li, and Jun-yan Gao wrote the manuscript.

Corresponding authors

Correspondence to Qin-wen Wang or Li-ping Li.

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Ethics Approval

All animal procedures were performed in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978) and approved by the Institutional Animal Care and Use Committee of the Ningbo University School of Medicine (SYXK(Zhe) 2013–0191).

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The authors declare no competing interests.

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Highlights

• Stimulation alleviates neurogenesis decline caused by Aβ oligomers in mice.

• Stimulation ameliorates Aβ oligomer-induced cognitive deficits in mice.

• Stimulation attenuates Aβ oligomer-induced anxiety- and depression-like behavior in mice.

• Stimulation inhibits Aβ oligomer-induced neurodegeneration through BDNF/TrkB signaling pathway.

• Stimulation improves glutamate metabolism, glycolysis, and tricarboxylic acid cycle in Aβ-induced mice.

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Li, Wy., Gao, Jy., Lin, SY. et al. Effects of Involuntary and Voluntary Exercise in Combination with Acousto-Optic Stimulation on Adult Neurogenesis in an Alzheimer's Mouse Model. Mol Neurobiol 59, 3254–3279 (2022). https://doi.org/10.1007/s12035-022-02784-9

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  • DOI: https://doi.org/10.1007/s12035-022-02784-9

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