CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation
Abstract Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein (CD2AP) gene is one of the most im...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Translational Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s40035-024-00454-5 |
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| author | Yan-Yan Xue Zhe-Sheng Zhang Rong-Rong Lin Hui-Fen Huang Ke-Qing Zhu Dian-Fu Chen Zhi-Ying Wu Qing-Qing Tao |
| author_facet | Yan-Yan Xue Zhe-Sheng Zhang Rong-Rong Lin Hui-Fen Huang Ke-Qing Zhu Dian-Fu Chen Zhi-Ying Wu Qing-Qing Tao |
| author_sort | Yan-Yan Xue |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein (CD2AP) gene is one of the most important genetic risk factors for AD. However, the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear. Methods The spatiotemporal expression pattern of CD2AP was determined. Then, we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion, using immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay, electrophysiology and behavioral tests. Additionally, we established a stable CD2AP-knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis. Finally, the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings. Results CD2AP is widely expressed in various regions of the mouse brain, with predominant expression in neurons and vascular endothelial cells. In APP/PS1 mice, neuronal knockout of Cd2ap significantly aggravated tau pathology, synaptic impairments and cognitive deficits. Mechanistically, the knockout of Cd2ap activated p38 mitogen-activated protein kinase (MAPK) signaling, which contributed to increased tau phosphorylation, synaptic injury, neuronal apoptosis and cognitive impairment. Furthermore, the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor. Conclusion Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway, identifying CD2AP/p38 MAPK as promising therapeutic targets for AD. |
| format | Article |
| id | doaj-art-c85e367037164d4482bf5a534a01e05d |
| institution | Kabale University |
| issn | 2047-9158 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj-art-c85e367037164d4482bf5a534a01e05d2025-01-19T12:36:50ZengBMCTranslational Neurodegeneration2047-91582024-12-0113112110.1186/s40035-024-00454-5CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activationYan-Yan Xue0Zhe-Sheng Zhang1Rong-Rong Lin2Hui-Fen Huang3Ke-Qing Zhu4Dian-Fu Chen5Zhi-Ying Wu6Qing-Qing Tao7Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryNational Health and Disease Human Brain Tissue Resource Center and Department of Pathology, School of Medicine, Zhejiang UniversityDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu LaboratoryAbstract Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein (CD2AP) gene is one of the most important genetic risk factors for AD. However, the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear. Methods The spatiotemporal expression pattern of CD2AP was determined. Then, we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion, using immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay, electrophysiology and behavioral tests. Additionally, we established a stable CD2AP-knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis. Finally, the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings. Results CD2AP is widely expressed in various regions of the mouse brain, with predominant expression in neurons and vascular endothelial cells. In APP/PS1 mice, neuronal knockout of Cd2ap significantly aggravated tau pathology, synaptic impairments and cognitive deficits. Mechanistically, the knockout of Cd2ap activated p38 mitogen-activated protein kinase (MAPK) signaling, which contributed to increased tau phosphorylation, synaptic injury, neuronal apoptosis and cognitive impairment. Furthermore, the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor. Conclusion Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway, identifying CD2AP/p38 MAPK as promising therapeutic targets for AD.https://doi.org/10.1186/s40035-024-00454-5Alzheimer’s diseaseCD2APP38 MAPKSynaptic injuryTau |
| spellingShingle | Yan-Yan Xue Zhe-Sheng Zhang Rong-Rong Lin Hui-Fen Huang Ke-Qing Zhu Dian-Fu Chen Zhi-Ying Wu Qing-Qing Tao CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation Translational Neurodegeneration Alzheimer’s disease CD2AP P38 MAPK Synaptic injury Tau |
| title | CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation |
| title_full | CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation |
| title_fullStr | CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation |
| title_full_unstemmed | CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation |
| title_short | CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation |
| title_sort | cd2ap deficiency aggravates alzheimer s disease phenotypes and pathology through p38 mapk activation |
| topic | Alzheimer’s disease CD2AP P38 MAPK Synaptic injury Tau |
| url | https://doi.org/10.1186/s40035-024-00454-5 |
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