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.