Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 Mice.

Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.