Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer’s Disease Pathogenesis

IF 2.4 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Neuroscience Pub Date : 2026-06-10 DOI:10.1007/s12031-026-02556-3

Hossein Shirvani, Linda S. Pescatello, Ali Reza Eftekhari Moghadam, Ehsan Arabzadeh

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引用次数: 0

Abstract

This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer’s disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30–45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy—affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein—including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails—remain speculative and are presented as future research directions rather than established therapeutic interventions.

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解锁神经保护：运动诱导的肌肉分泌组（Myokines）作为对抗阿尔茨海默病发病机制的治疗途径。

这篇综述严格评估了运动诱导的肌因子作为抗阿尔茨海默病（AD）神经保护剂的作用，并围绕三个主题部分进行了架构：(1)肌因子神经保护的机制基础，(2)治疗开发的转化障碍，以及(3)未来研究的战略框架。流行病学研究将体育锻炼与阿尔茨海默病风险降低（30-45%）联系起来，但机制尚未完全解决。临床前研究表明，运动诱导的肌因子（鸢尾素，BDNF，组织蛋白酶B）通过以下方式调节AD病理：(1)减少淀粉样蛋白- β (Aβ)/tau积累，(2)抑制神经炎症，(3)增强突触可塑性。然而，人类运动干预显示出受APOE基因型、年龄和运动方式影响的相互矛盾的结果。相关的人类数据表明，白细胞介素-6 （IL-6）具有多效性，在急性情况下具有神经保护作用，但在慢性炎症状态下具有潜在的有害作用。治疗障碍包括血脑屏障（BBB）渗透、多效性风险和患者异质性。新兴概念，如组合方法（纳米载体，运动模拟物）和生物标志物驱动的试验被提议作为假设的未来策略；然而，这些仍然未经验证，需要大量的临床前开发才能在临床护理中实施。这篇叙述性综述围绕三个主题部分进行：肌因子神经保护的机制基础，治疗开发的翻译障碍，以及未来研究的战略框架。肌脑轴是一个引人注目但复杂的治疗靶点。基于目前的临床前和相关的人类证据，未来的研究应优先考虑机制的严谨性、标准化的生物标志物验证和临床可行的给药策略。值得注意的是，本文讨论的几种方法——包括纳米载体递送系统、运动模拟物和组合肌因子鸡尾酒疗法——仍然是推测性的，是未来的研究方向，而不是既定的治疗干预措施。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Neuroscience 医学-神经科学

CiteScore

6.60

自引率

3.20%

发文量

142

审稿时长

1 months

期刊介绍： The Journal of Molecular Neuroscience is committed to the rapid publication of original findings that increase our understanding of the molecular structure, function, and development of the nervous system. The criteria for acceptance of manuscripts will be scientific excellence, originality, and relevance to the field of molecular neuroscience. Manuscripts with clinical relevance are especially encouraged since the journal seeks to provide a means for accelerating the progression of basic research findings toward clinical utilization. All experiments described in the Journal of Molecular Neuroscience that involve the use of animal or human subjects must have been approved by the appropriate institutional review committee and conform to accepted ethical standards.