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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Both AD model mice established by injecting A\u03b2\u2084\u2082 oligomers into hippocampus and APP\/PS1 AD transgenic mice were used. Mice were subjected to treadmill training, 40\u00a0Hz 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 A\u03b2\u2084\u2082 oligomers, outperforming single-modality treatments. It markedly diminished hippocampal accumulation of \u03b2-amyloid (A\u03b2) 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 A\u03b2 and cognitive defects of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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 A\u03b2 deposition and cognitive defect of AD mice. This study highlights the significant therapeutic potential of multimodal, non-pharmacological strategies for Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13195-026-02075-8","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:54:52Z","timestamp":1780030492000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical exercise in combination with audiovisual stimulation alleviates cognitive and affective impairments in Alzheimer\u2019s disease model mice via restoring lysosomal membrane integrity"],"prefix":"10.1186","volume":"18","author":[{"given":"Jun","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guomin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunshuang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoxia","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinkai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingsong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"2075_CR1","doi-asserted-by":"crossref","unstructured":"2024 Alzheimer\u2019s disease facts and figures. 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