Aerobic Exercise Training Exerts Neuroprotective Effects in Alzheimer's Disease Mice by Regulating Endoplasmic Reticulum Stress-Autophagy Pathway-Mediated Pyroptosis

Objective: This study probed into the neuroprotective effects of aerobic exercise training (AET) on Alzheimer's disease (AD) mice and further explored the molecular mechanisms through which AET regulates the endoplasmic reticulum stress (ERS)-autophagy pathway to mediate Pyroptosis.

Methods: APP/PS1 mice (AD model) underwent 8 weeks of treadmill-based AET. In addition to the exercise regimen, mice were treated with intraperitoneal injections of an NLRP3 inflammasome activator, an Autophagy inhibitor, an ERS inducer, and a PERK activator for assessing cognitive function and neuronal damage in the hippocampal CA1 region through cognitive assessments, histological analyses, and biochemical assays. BrdU/EdU labeling combined with NeuN and doublecortin immunostaining was used to evaluate AET-stimulated neuronal proliferation and differentiation in the hippocampus.

Results: AET improved cognitive function in AD mice. Following AET, neuronal damage in the hippocampal CA1 region was reduced, the number of Nissl bodies increased, and Aβ_1-42 and p-Tau protein levels decreased. Mechanistically, AET alleviated NLRP3 inflammasome-mediated Pyroptosis and cognitive dysfunction in AD mice by inhibiting ERS and promoting Autophagy in the hippocampal CA1 region. Activation of the NLRP3 inflammasome or inhibition of Autophagy partially reversed the beneficial effects of AET on Pyroptosis and cognitive dysfunction in AD mice. Moreover, AET reduced ERS by inhibiting the PERK-eIF2α pathway, thereby enhancing Autophagy, reducing Pyroptosis, and improving cognitive dysfunction.

Conclusion: AET reduces NLRP3 inflammasome-mediated Pyroptosis and neuronal damage in the hippocampal CA1 region of AD mice by regulating the ERS-autophagy pathway through the inhibition of the PERK-eIF2α pathway, thereby improving cognitive function in AD mice.