Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice

Abstract

Physical exercise improves memory and cognition in physiological aging and Alzheimer’s disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aβ oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3β, Aβ oligomers (Aβ dimers and trimers), pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3β kinase activity, decreases in the levels of Aβ oligomers, pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3β kinase activity.

Treadmill running on neuropathic pain: via modulation of neuroinflammation

“…Loreto et al found that treadmill exercise can activate the anti-amyloidogenic production pathway in mice, reducing the accumulation of Aβ ( Di Loreto et al, 2014 ). After 12 weeks of treadmill training, AD model mice showed considerable decrease in the levels of oligomers (Aβ dimers and trimers) and pro-inflammatory cytokines (including IL-1β, IL-6, and TNF-α) ( Mu et al, 2022 ). Given the pathological contribution of amyloid protein to neuropathic pain, this change may reduce the activation of microglia and the release of pro-inflammatory factors and can thereby alleviate neuropathic pain.…”

“…In addition, the expression levels of microglia and astrocytes in CCI sciatic nerve mice decreased after short-term treadmill exercise, which may have alleviated neuropathic pain by improving the excessive activation of microglia during neuroinflammation ( Cobianchi et al, 2010 ). Furthermore, treadmill running can inhibit the excessive activation of astrocytes and microglia by inhibiting the activity of GSK3β kinase, thereby reducing the production of pro-inflammatory cytokines and relieving neuropathic pain ( Mu et al, 2022 ). Overall, we can conclude that treadmill training can relieve neuropathic pain by regulating the levels of inflammatory cytokines and the activation of glial cells.…”

Editorial: The impact of physical activity on white matter during healthy aging

“…These changes appear to be accompanied by improved memory and cerebrovascular regulation (Guadagni et al, 2020 ), in association with an increase of BDNF in the bloodstream (Binder and Scharfman, 2004 ), ensuring that brain tissue consistently receives adequate blood supply to meet its needs and preserve its function. Furthermore, moderate physical activity, i.e., treadmill exercise, reduces neuroinflammation and glial cell activation, decreases amyloid β oligomers levels and improves synaptic transmission in the prefrontal cortex in transgenic (3 ×) mouse models of Alzheimer's disease, possibly related to the inhibition of GSK3β kinase activity (Mu et al, 2022 ). This provides direct evidence of physical activity modulating the extent of known Alzheimer's disease hallmarks, amyloid and neurofibrillary pathology, as well as synaptic loss.…”