Abstract Background Alzheimer's disease (AD) is a progressive disorder characterized by cognitive decline. Physical exercise and audiovisual stimulation have gained increasing concern for their potential to mitigate AD pathology. However, the therapeutic advantages of combining these interventions and the precise molecular mechanisms underlying these strategies need further demonstration. Objectives This study aimed to assess the protective effects and underlying mechanisms of physical exercise combined with audiovisual stimulation on cognitive and affective functions, as well as on pathological alterations in AD mice. Methods AD model mice were established by injecting Aβ₄₂ oligomers into hippocampus. Mice were subjected to treadmill training, 40 Hz audio-visual stimulation, or a combination of these interventions, respectively. After the interventions, the cognitive and anxiety/depression-like behaviors were evaluated by novel object recognition, morris water maze, open field, tail suspension, or forced swimming, respectively. Quantitative proteomics combined with molecular analyses and transmission electron microscopy were used to systematically evaluate the underlying mechanism of multimodal interventions in AD model mice. Results The multimodal intervention significantly prevented cognitive impairment and ameliorated anxiety/depression-like behaviors in AD mice, outperforming single-modality treatments. It markedly diminished hippocampal accumulation of β-amyloid (Aβ) and tau phosphorylation in AD mice. Proteomic analyses revealed that multimodal intervention exerted a more comprehensive restoration of dysregulated proteins in AD mice compared to single-modality interventions. The interventions have synergetic effects in decreasing inflammation reactions and restoring the autophagy-lysosomal function. Multimodal intervention upregulated the expression levels of LAMP1 and TFEB, and concurrently increased HSPA1L expression to restore lysosomal membrane integrity. The degradation function of lysosomes was also improved by multimodal intervention as revealed by the decreased LC3II/I ratio, reduced p62 level, as well as alleviated lysosome enlargement in AD mice. Conclusion Physical exercise and audiovisual stimulation exert synergistic effects in decreasing inflammation reaction and maintaining autophagy-lysosomal homeostasis via increasing the biogenesis of lysosomes and restoring the integrity of lysosome membrane, thereby reducing Aβ deposition and tau pathologies. This study highlights the significant therapeutic potential of multimodal, non-pharmacological strategies for Alzheimer’s disease.
Jia et al. (Tue,) studied this question.