Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
J Cell Physiol. 2023 May;238(5):954-965. doi: 10.1002/jcp.31005. Epub 2023 Apr 3.
The mechanisms of autophagy have been related to Alzheimer's disease (AD) pathogenesis by the endosomal-lysosomal system, having a critical function in forming amyloid-β (Aβ) plaques. Nevertheless, the exact mechanisms mediating disease pathogenesis remain unclear. The transcription factor EB (TFEB), a primary transcriptional autophagy regulator, improves gene expression, mediating lysosome function, autophagic flux, and autophagosome biogenesis. In this review, we present for the first time the hypothesis of how TFEB, autophagy, and mitochondrial function are interconnected in AD, providing a logical foundation for unraveling the critical role of chronic physical exercise in this process. Aerobic exercise training promotes Adiponectin Receptor 1 (AdipoR1)/AMP-activated protein kinase (AMPK)/TFEB axis activation in the brain of the AD animal model, which contributes to alleviated Aβ deposition and neuronal apoptosis while improving cognitive function. Moreover, TFEB upregulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear factor erythroid 2-related factor 2 (NRF-2), improving mitochondrial biogenesis and redox status. In addition, tissue contraction activates calcineurin in skeletal muscle, which induces TFEB nuclear translocation, raising the hypothesis that the same would occur in the brain. Thus, a deep and comprehensive exploration of the TFEB could provide new directions and strategies for preventing AD. We conclude that chronic exercise can be an effective TFEB activator, inducing autophagy and mitochondrial biogenesis, representing a potential nonpharmacological strategy contributing to brain health.
自噬的机制通过内体溶酶体系统与阿尔茨海默病（AD）的发病机制有关，在形成淀粉样β（Aβ）斑块方面具有关键作用。然而，介导疾病发病机制的确切机制仍不清楚。转录因子 EB（TFEB）是一种主要的转录自噬调节剂，可改善基因表达，调节溶酶体功能、自噬流和自噬体生物发生。在这篇综述中，我们首次提出了 TFEB、自噬和线粒体功能在 AD 中相互关联的假设，为揭示慢性体力活动在这一过程中的关键作用提供了逻辑基础。有氧运动训练可促进 AD 动物模型大脑中脂联素受体 1（AdipoR1）/AMP 激活蛋白激酶（AMPK）/TFEB 轴的激活，有助于减轻 Aβ沉积和神经元凋亡，同时改善认知功能。此外，TFEB 上调过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）和核因子红细胞 2 相关因子 2（NRF-2），改善线粒体生物发生和氧化还原状态。此外，组织收缩可激活骨骼肌中的钙调神经磷酸酶，诱导 TFEB 核易位，这就提出了一个假设，即同样的情况也会发生在大脑中。因此，深入全面地研究 TFEB 可以为预防 AD 提供新的方向和策略。我们得出结论，慢性运动可以有效地激活 TFEB，诱导自噬和线粒体生物发生，代表了一种促进大脑健康的潜在非药物策略。
