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Exercise Rehabilitation and/or Astragaloside Attenuate Amyloid-beta Pathology by Reversing BDNF/TrkB Signaling Deficits and Mitochondrial Dysfunction

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A Correction to this article was published on 03 May 2022

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Abstract

We aim to investigate the mechanisms underlying the beneficial effects of exercise rehabilitation (ER) and/or astragaloside (AST) in counteracting amyloid-beta (Aβ) pathology. Aβ oligomers were microinjected into the bilateral ventricles to induce Aβ neuropathology in rats. Neurobehavioral functions were evaluated. Cortical and hippocampal expressions of both BDNF/TrkB and cathepsin D were determined by the western blotting method. The rat primary cultured cortical neurons were incubated with BDNF and/or AST and ANA12 followed by exposure to aggregated Aβ for 24 h. In vivo results showed that ER and/or AST reversed neurobehavioral disorders, downregulation of cortical and hippocampal expression of both BDNF/TrkB and cathepsin D, neural pathology, Aβ accumulation, and altered microglial polarization caused by Aβ. In vitro studies also confirmed that topical application of BDNF and/or AST reversed the Aβ-induced cytotoxicity, apoptosis, mitochondrial distress, and synaptotoxicity and decreased expression of p-TrkB, p-Akt, p-GSK3β, and β-catenin in rat cortical neurons. The beneficial effects of combined ER (or BDNF) and AST therapy in vivo and in vitro were superior to ER (or BDNF) or AST alone. Furthermore, we observed that any gains from ER (or BDNF) and/or AST could be significantly eliminated by ANA-12, a potent BDNF/TrkB antagonist. These results indicate that whereas ER (or BDNF) and/or AST attenuate Aβ pathology by reversing BDNF/TrkB signaling deficits and mitochondrial dysfunction, combining these two potentiates each other’s therapeutic effects. In particular, AST can be an alternative therapy to replace ER.

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Abbreviations

Aβ:

Amyloid-beta

p-Akt:

Phosphorylated serine/threonine-protein kinase

T-Akt:

Total form serine/threonine-protein kinase

ANA12:

N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl] benzo[b]thiophene-2-carboxamide

AST:

Astragaloside

BDNF:

Brain-derived neurotrophic factor

CTSD:

Cathepsin D

DAPI:

4′,6-Diamidino-2-phenylindole

ECL:

Enhanced chemiluminescence

ER:

Exercise rehabilitation

GSK3β:

Glycogen synthase kinase-3 beta

i.c.v.:

Intracerebroventricular

i.p.:

Intraperitoneal

Iba-1:

Ionized calcium-binding adaptor molecule 1

NeuN:

Neuronal nuclei

PBS:

Phosphate-buffered saline

RIPA:

Radioimmunoprecipitation assay buffer

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

p-TrkB:

Phosphorylated tropomyosin receptor kinase B

T-TrkB:

Total tropomyosin receptor kinase B

TUNEL:

Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling

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Acknowledgements

We acknowledge Ms. Meng-Tsung Ho for her excellent editorial assistance in manuscript preparation.

Funding

This study was supported by the Taiwan Ministry of Science and Technology (MOST) (grant no. MOST109-2314-B-384–002-MY3, MOST106-2314-B-384 -001 -MY3, MOST 105–2314-B-384 -001 -MY3) and Chi Mei Medical Center (Taiwan) grant CMFHT10802. The funders had no role in the study design, data collection, and analysis, the decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Physical Medicine and Rehabilitation, Chi-Mei Medical Center, Tainan, Taiwan

    Yu-Lin Wang

  2. Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Yu-Lin Wang

  3. Division of Neurosurgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan

    Chung-Ching Chio & Chao-Hung Yeh

  4. Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan

    Shu-Chun Kuo

  5. Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan

    Shu-Chun Kuo & Chao-Hung Yeh

  6. Department of Medical Research, Chi Mei Medical Center, No. 901, Zhonghua Rd, Yongkang District, Tainan City 710, Taiwan

    Jui-Ti Ma, Wen-Pin Liu, Mao-Tsun Lin & Ching-Ping Chang

  7. Department of Holistic Care, Chi Mei Medical Center, No. 901, Zhonghua Rd, Yongkang District, Tainan City 710, Taiwan

    Kao-Chang Lin

  8. Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan

    Kao-Chang Lin

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Contributions

Study concept and design: WYL, SCK, CCC; acquisition of data: CHY, JTM, WPL; analysis and interpretation of data: WYL, SCK, CHY; drafting of the manuscript: CCC, CPC, KCL; critical revision of the manuscript for important intellectual content: SCK, CCC, MTL; statistical analysis: WYL, JTM, WPL; material support: CCC, CPC, MTL; obtained funding: CCC, CPC, KCL. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Kao-Chang Lin or Ching-Ping Chang.

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All animal experiments were approved and carried out in accordance with the Institutional Animal Care and Use Committee at the Chi Mei Medical Center, Tainan, Taiwan (approved no. 108120110).

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Wang, YL., Chio, CC., Kuo, SC. et al. Exercise Rehabilitation and/or Astragaloside Attenuate Amyloid-beta Pathology by Reversing BDNF/TrkB Signaling Deficits and Mitochondrial Dysfunction. Mol Neurobiol 59, 3091–3109 (2022). https://doi.org/10.1007/s12035-022-02728-3

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