Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis
Abstract Background Aging is the greatest risk factor for late-onset Alzheimer’s disease (LOAD), which accounts for > 95% of all Alzheimer’s disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase c...
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BMC
2025-06-01
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| Series: | Translational Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s40035-025-00487-4 |
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| author | Ling Lei Yilei Cheng Anqi Yin Jian-Min Han Gang Wu Fumin Yang Qi Wang Jian-Zhi Wang Rong Liu Hong-Lian Li Xiaochuan Wang |
| author_facet | Ling Lei Yilei Cheng Anqi Yin Jian-Min Han Gang Wu Fumin Yang Qi Wang Jian-Zhi Wang Rong Liu Hong-Lian Li Xiaochuan Wang |
| author_sort | Ling Lei |
| collection | DOAJ |
| description | Abstract Background Aging is the greatest risk factor for late-onset Alzheimer’s disease (LOAD), which accounts for > 95% of all Alzheimer’s disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear. Methods AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague–Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test. Results YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects. Conclusions These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD. |
| format | Article |
| id | doaj-art-5f1178b5147f4c94a74a7947228b5dc7 |
| institution | OA Journals |
| issn | 2047-9158 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Translational Neurodegeneration |
| spelling | doaj-art-5f1178b5147f4c94a74a7947228b5dc72025-08-20T02:05:39ZengBMCTranslational Neurodegeneration2047-91582025-06-0114111910.1186/s40035-025-00487-4Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axisLing Lei0Yilei Cheng1Anqi Yin2Jian-Min Han3Gang Wu4Fumin Yang5Qi Wang6Jian-Zhi Wang7Rong Liu8Hong-Lian Li9Xiaochuan Wang10Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityWuhan Sixth Hospital Affiliated to Jianghan UniversitySchool of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversitySchool of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologySchool of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan UniversityAbstract Background Aging is the greatest risk factor for late-onset Alzheimer’s disease (LOAD), which accounts for > 95% of all Alzheimer’s disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear. Methods AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague–Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test. Results YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects. Conclusions These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.https://doi.org/10.1186/s40035-025-00487-4YAP1Nr4a1Alzheimer’s diseaseSenescence |
| spellingShingle | Ling Lei Yilei Cheng Anqi Yin Jian-Min Han Gang Wu Fumin Yang Qi Wang Jian-Zhi Wang Rong Liu Hong-Lian Li Xiaochuan Wang Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis Translational Neurodegeneration YAP1 Nr4a1 Alzheimer’s disease Senescence |
| title | Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis |
| title_full | Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis |
| title_fullStr | Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis |
| title_full_unstemmed | Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis |
| title_short | Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis |
| title_sort | aging dependent yap1 reduction contributes to ad pathology by upregulating the nr4a1 akt gsk 3β axis |
| topic | YAP1 Nr4a1 Alzheimer’s disease Senescence |
| url | https://doi.org/10.1186/s40035-025-00487-4 |
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