iProXProteomicsShujun XuMus Musculushttp://www.iprox.org/page/project.html?id=IPX0016828000xushujun@nbu.edu.cnNingbo UniversityiProX<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>Both AD model mice established by injecting Aβ₄₂ oligomers into hippocampus and APP/PS1 AD transgenic mice were used. 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.<h4>Results</h4>The multimodal intervention significantly prevented cognitive impairment and ameliorated anxiety/depression-like behaviors of APP/PS1 AD transgenic mice and AD model mice induced by injecting Aβ₄₂ oligomers, outperforming single-modality treatments. It markedly diminished hippocampal accumulation of β-amyloid (Aβ) and tau phosphorylation in AD mice. Multiple interventions also reversed synapse loss of 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 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. Upregulation of HSPA1L reversed the disruption of lysosome membrane integrity of AD transegenic mice, thereby reversed the increased accumulation of Aβ and cognitive defects of AD.<h4>Conclusion</h4>Physical exercise and audiovisual stimulation exert synergistic effects in decreasing the inflammation reaction and maintaining autophagy-lysosomal homeostasis by increasing the biogenesis of lysosomes and restoring the integrity of lysosome membrane, thereby reducing Aβ deposition and cognitive defect of AD mice. This study highlights the significant therapeutic potential of multimodal, non-pharmacological strategies for Alzheimer's disease.Physical exercise in combination with audiovisual stimulation alleviates cognitive and affective impairments in Alzheimer's disease model mice via restoring lysosomal membrane integrity.Jia Jun J, Xie Guomin G, Zheng Wu W, Xu Chunshuang C, Xia Yuxin Y, Hu Qiaoxia Q, Xiang Binbin B, Zhou Xinkai X, Chen Anqi A, Chen Xiaoping X, Wang Qinwen Q, Zhou Yingsong Y, Xu Shujun SfalsePhysical exercise in combination with audiovisual stimulation alleviates cognitive and affective impairments in Alzheimer's disease model miceThis project focus on the proteomic changes in AD model mice. AD model mice were established by injecting Aβ₄₂ oligomers into the hippocampus. These mice were then subjected to treadmill training(ADE), 40 Hz audio-visual stimulation(ADVL), or a combination of these interventions(ADEVL). Quantitative proteomics, combined with behavioral tests and molecular analyses, were utilized to evaluate the underlying therapeutic mechanisms of these multimodal interventions in the Aβ₄₂-induced AD model.Mon Apr 27 00:00:00 GMT+01:00 2026PXD0776851009042216028