Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway
Abstract Background The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer’s disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer’s disease (FAD); howeve...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-022-00874-8 |
| _version_ | 1811320767117262848 |
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| author | Cheong-Meng Chong Yuan Tan Jiaqi Tong Minjing Ke Ke Zhang Lingli Yan Xiaotong Cen Jia-Hong Lu Guobing Chen Huanxing Su Dajiang Qin |
| author_facet | Cheong-Meng Chong Yuan Tan Jiaqi Tong Minjing Ke Ke Zhang Lingli Yan Xiaotong Cen Jia-Hong Lu Guobing Chen Huanxing Su Dajiang Qin |
| author_sort | Cheong-Meng Chong |
| collection | DOAJ |
| description | Abstract Background The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer’s disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer’s disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue. Methods We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining. Results Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons. Conclusion We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD. |
| first_indexed | 2024-04-13T13:05:11Z |
| format | Article |
| id | doaj.art-755c73d220034150b8ead9b0e7fa98f7 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-13T13:05:11Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-755c73d220034150b8ead9b0e7fa98f72022-12-22T02:45:47ZengBMCCell & Bioscience2045-37012022-08-0112111510.1186/s13578-022-00874-8Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathwayCheong-Meng Chong0Yuan Tan1Jiaqi Tong2Minjing Ke3Ke Zhang4Lingli Yan5Xiaotong Cen6Jia-Hong Lu7Guobing Chen8Huanxing Su9Dajiang Qin10State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauInstitute of Geriatric Immunology, School of Medicine, Jinan UniversityState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical UniversityAbstract Background The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer’s disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer’s disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue. Methods We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining. Results Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons. Conclusion We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD.https://doi.org/10.1186/s13578-022-00874-8mTORPresenilin-1iPSCCRISPR/Cas9 |
| spellingShingle | Cheong-Meng Chong Yuan Tan Jiaqi Tong Minjing Ke Ke Zhang Lingli Yan Xiaotong Cen Jia-Hong Lu Guobing Chen Huanxing Su Dajiang Qin Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway Cell & Bioscience mTOR Presenilin-1 iPSC CRISPR/Cas9 |
| title | Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway |
| title_full | Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway |
| title_fullStr | Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway |
| title_full_unstemmed | Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway |
| title_short | Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway |
| title_sort | presenilin 1 f105c mutation leads to tau accumulation in human neurons via the akt mtorc1 signaling pathway |
| topic | mTOR Presenilin-1 iPSC CRISPR/Cas9 |
| url | https://doi.org/10.1186/s13578-022-00874-8 |
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