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Review
. 2022 Jun;17(6):1210-1227.
doi: 10.4103/1673-5374.325012.

All roads lead to Rome - a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer's disease

Yi-Yao Liang  1 , Li-Dan Zhang  1 , Xi Luo  1 , Li-Li Wu  2 , Zhao-Wei Chen  3 , Guang-Hao Wei  3 , Kai-Qing Zhang  3 , Ze-An Du  4 , Ren-Zhi Li  5 , Kwok-Fai So  6 , Ang Li  7
Affiliations
Review

All roads lead to Rome - a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer's disease

Yi-Yao Liang et al. Neural Regen Res. 2022 Jun.

Abstract

Age-related neurodegenerative disorders such as Alzheimer's disease (AD) have become a critical public health issue due to the significantly extended human lifespan, leading to considerable economic and social burdens. Traditional therapies for AD such as medicine and surgery remain ineffective, impractical, and expensive. Many studies have shown that a variety of bioactive substances released by physical exercise (called "exerkines") help to maintain and improve the normal functions of the brain in terms of cognition, emotion, and psychomotor coordination. Increasing evidence suggests that exerkines may exert beneficial effects in AD as well. This review summarizes the neuroprotective effects of exerkines in AD, focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise. The findings described in this review will help direct research into novel _targets for the treatment of AD and develop customized exercise therapy for individuals of different ages, genders, and health conditions.

Keywords: Alzheimer's disease; Tau protein; amyloid beta; central nervous system; exerkine; neurodegeneration; neuroinflammation; neuroprotection; oxidative stress; physical exercise.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
Theories regarding the pathogenesis of AD. (A) Amyloid-β plaque theory. APP is degraded into Aβ monomers, which then assemble into Aβ oligomers and ultimately pathological Aβ plaques. (B) Tau NFT theory. Abnormal post-translational modification of Tau (especially hyperphosphorylation) promotes Tau-Tau interactions, leading to the sequential formation of tangles, PHFs, and NFTs. (C) Neuroinflammation theory. Quiescent immune cells in the CNS (mainly microglia and astrocytes) can be activated by toxic Aβ aggregates and then secrete a large number of proinflammatory cytokines, leading to chronic inflammation. (D) Oxidative stress theory. Certain pathological stimuli (e.g., Aβ plaques and NFTs) can disrupt metal homeostasis and mitochondrial dysfunction, both of which increase ROS generation and cause neurodegeneration due to oxidative injury. These four mechanisms may work independently or interactively, eventually resulting in AD pathology, including cerebral cortical shrinkage, ventricular enlargement, and hippocampal atrophy. AD: Alzheimer’s disease; APP: amyloid precursor protein; Aβ: beta-amyloid peptide; CNS: central nervous system; NFT: neurofibrillary tangle; PHF: paired helical filament; ROS: reactive oxygen species.
Figure 2
Figure 2
How physical exercise may benefit AD brains. Physical exercise triggers the release of numerous exerkines from peripheral tissues/organs. Most of these exerkines can permeate through the blood-brain barrier and elicit a variety of biological changes in the central nervous system, such as a reduction in oxidative stress, phosphorylation of Tau, and neuroinflammation, while enhancing Aβ clearance, synaptic plasticity, and neurogenesis. These processes can be neuroprotective and thereby mitigate AD pathology. The exerkines shown in the upper right panel are color-coded to correspond to the main tissue/organ of origin, as shown in the upper left panel. The exerkine numbers shown in the upper right panel correspond with the numbers shown in parentheses in the lower panel, indicating the reported neuroprotective mechanisms of these exerkines with regard to mitigating AD pathology. AD: Alzheimer’s disease; ADN: adiponectin; Aβ: beta-amyloid peptide; BDNF: brain-derived neurotrophic factor; CNS: central nervous system; FNDC5: fibronectin type III domain containing 5; GSH: glutathione; IDE: insulin-degrading enzyme; IGF-1: insulin-like growth factor 1; KYNA: kynurenic acid; miRNA: microRNA; NEP: neprilysin; NGF: nerve growth factor; SOD: superoxide dismutase; VEGF: vascular endothelial growth factor.
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