Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models
Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence disease progression. Still, the molecular mechanisms caused by different mutations of AD are not understood. We have performed a multidisciplinary study to investiga...
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Nature Publishing Group
2025-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03321-7 |
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| author | Huda Suloh Shashank Kumar Ojha Maryam Kartawy Wajeha Hamoudi Manish Kumar Tripathi Wisam Bazbaz Nofar Schottlender Uri Ashery Igor Khaliulin Haitham Amal |
| author_facet | Huda Suloh Shashank Kumar Ojha Maryam Kartawy Wajeha Hamoudi Manish Kumar Tripathi Wisam Bazbaz Nofar Schottlender Uri Ashery Igor Khaliulin Haitham Amal |
| author_sort | Huda Suloh |
| collection | DOAJ |
| description | Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence disease progression. Still, the molecular mechanisms caused by different mutations of AD are not understood. We have performed a multidisciplinary study to investigate and compare the early stages of the pathology in two transgenic AD mouse models: P301S and 5xFAD. Using SNOTRAP-based mass spectrometry, we assessed changes in S-nitrosylation, a nitric oxide-mediated post-translational modification, of proteins in both models during their juvenile age. The increased levels of 3-nitrotyrosine confirmed nitrosative stress in the mutant mice. Systems biology analysis revealed shared processes between the models, particularly in the γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission processes. In the P301S model, we identified 273 S-nitrosylated (SNOed) proteins in the cortex, with 244 proteins uniquely SNOed in the diseased mice. In the 5xFAD model, 309 SNOed proteins were identified. We have found altered proteins expression of different glutamate/GABA-related markers in the cortex and hippocampus of both AD mouse models. Additionally, the phosphorylation levels of the mTOR signaling components revealed hyperactivation of this pathway in P301S mice. Conversely, 5xFAD mice showed no significant changes in mTOR signaling except for elevated phosphorylation of the ribosomal protein S6 in the cortex. Our findings revealed key molecular mechanisms in the two AD mouse models during their early stages. These mechanisms could serve as potential biomarkers and therapeutic targets for early-stage AD. |
| format | Article |
| id | doaj-art-939a46a0f44546b1b09b3ca964101710 |
| institution | DOAJ |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-939a46a0f44546b1b09b3ca9641017102025-08-20T02:49:16ZengNature Publishing GroupTranslational Psychiatry2158-31882025-03-0115111110.1038/s41398-025-03321-7Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse modelsHuda Suloh0Shashank Kumar Ojha1Maryam Kartawy2Wajeha Hamoudi3Manish Kumar Tripathi4Wisam Bazbaz5Nofar Schottlender6Uri Ashery7Igor Khaliulin8Haitham Amal9Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemSchool of Neurobiology, Biochemistry and Biophysics, Life Sciences Faculty, Tel Aviv UniversitySchool of Neurobiology, Biochemistry and Biophysics, Life Sciences Faculty, Tel Aviv UniversityInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemInstitute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemAbstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence disease progression. Still, the molecular mechanisms caused by different mutations of AD are not understood. We have performed a multidisciplinary study to investigate and compare the early stages of the pathology in two transgenic AD mouse models: P301S and 5xFAD. Using SNOTRAP-based mass spectrometry, we assessed changes in S-nitrosylation, a nitric oxide-mediated post-translational modification, of proteins in both models during their juvenile age. The increased levels of 3-nitrotyrosine confirmed nitrosative stress in the mutant mice. Systems biology analysis revealed shared processes between the models, particularly in the γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission processes. In the P301S model, we identified 273 S-nitrosylated (SNOed) proteins in the cortex, with 244 proteins uniquely SNOed in the diseased mice. In the 5xFAD model, 309 SNOed proteins were identified. We have found altered proteins expression of different glutamate/GABA-related markers in the cortex and hippocampus of both AD mouse models. Additionally, the phosphorylation levels of the mTOR signaling components revealed hyperactivation of this pathway in P301S mice. Conversely, 5xFAD mice showed no significant changes in mTOR signaling except for elevated phosphorylation of the ribosomal protein S6 in the cortex. Our findings revealed key molecular mechanisms in the two AD mouse models during their early stages. These mechanisms could serve as potential biomarkers and therapeutic targets for early-stage AD.https://doi.org/10.1038/s41398-025-03321-7 |
| spellingShingle | Huda Suloh Shashank Kumar Ojha Maryam Kartawy Wajeha Hamoudi Manish Kumar Tripathi Wisam Bazbaz Nofar Schottlender Uri Ashery Igor Khaliulin Haitham Amal Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models Translational Psychiatry |
| title | Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models |
| title_full | Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models |
| title_fullStr | Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models |
| title_full_unstemmed | Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models |
| title_short | Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer’s disease mouse models |
| title_sort | shared early molecular mechanisms revealed in p301s and 5xfad alzheimer s disease mouse models |
| url | https://doi.org/10.1038/s41398-025-03321-7 |
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