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miR-34a/TAN1/CREB Axis Engages in Alleviating Oligodendrocyte Trophic Factor-Induced Myelin Repair Function and Astrocyte-Dependent Neuroinflammation in the Early Stages of Alzheimer's Disease: The Anti-Neurodegenerative Effect of Treadmill Exercise

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Abstract

Reduced myelin stability observed in the early stages of Alzheimer's disease leads to spatial learning and memory impairment. Exercise has been shown to protect nerves, reduce the risk of Alzheimer's disease, and strengthen synaptic connectivity. However, the underlying mechanisms of how exercise can promote myelin repair and coordinate inflammation and proliferation are still uncertain. In this study, we conducted histological and biochemical assays of cortical lysates after behavioral testing to detect pathological changes, myelin sheath thickness, and mRNA and protein levels. It is notable that D-galactose model mice exhibited elevated miRNA-34a levels, overactive astrocytes, decreased myelin staining scores, increased apoptosis, and decreased synaptic plasticity in the brain. Significantly, after eight weeks of exercise, we observed improvements in LFB scores, NeuN( +) neuron counts, and myelin basic protein (MBP) expression. Additionally, exercise promoted the expression of oligodendrocyte markers Olig2 and PDFGR-α associated with brain proliferation, and improved spatial cognitive function. Furthermore, it decreased the inflammation caused by astrocyte secretions (TNF-α, Cox-2, CXCL2). Interestingly, we also observed downregulation of miR-34a and activation of the TAN1/PI3K/CREB signaling pathway. Our data shed light on a previously unsuspected mechanism by which exercise reduces miR-34a levels and protects neuronal function and survival by preventing excessive demyelination and inflammatory infiltration in the CNS.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

miR-34a:

MicroRNA-34a

D-Gal:

D-galactose

AD:

Alzheimer's disease

NFTs:

Neurofibrillary tangles

LFB:

Luxol Fast Blue

MWM:

Morries water maze

Cox-2:

Cyclooxygenase-2

CXCL2:

C-X-C Motif Chemokine Ligand 2

PDGFR:

Platelet derived growth factor receptor alpha

MBP:

Myelin basic protein

TAN1:

Translocation-associated notch protein TAN-1

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

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Acknowledgements

The animal study protocol was approved by the Biomedical Research Ethics Committee of Hunan Normal University (Ethics Section 2021 No. 365).

Funding

This research was funded by National Natural Science Foundation of China, grant number: 32371182.

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Authors and Affiliations

  1. Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, 529 LuShanNan Road, Changsha, 410012, China

    Yang Liu, Xiao-Kang Meng, Wen-zhen Shao, Chao Tang, Si-si Deng, Chang-fa Tang, Lan Zheng & Wen Guo

  2. Hunan Province Sports Public Service Research Base, Hunan Normal University, Changsha, 410012, China

    Chang-fa Tang

  3. Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, 266071, China

    Ya-qun Liu

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  1. Yang Liu
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All authors contributed significantly to this research and preparation of the manuscript. YL, WG, LZ, and (Chang-fa Tang) CT conceived and designed the experiments and wrote the manuscript. YL, XM, SD, and CT performed the experiments and analyzed the data; YL, WS edited and revised manuscript. YL is the first author to the work. All authors have been involved in the final approval of the manuscript for publication.

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Correspondence to Wen Guo.

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Liu, Y., Meng, XK., Shao, Wz. et al. miR-34a/TAN1/CREB Axis Engages in Alleviating Oligodendrocyte Trophic Factor-Induced Myelin Repair Function and Astrocyte-Dependent Neuroinflammation in the Early Stages of Alzheimer's Disease: The Anti-Neurodegenerative Effect of Treadmill Exercise. Neurochem Res 49, 1105–1120 (2024). https://doi.org/10.1007/s11064-024-04108-w

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