Academic Journal
Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer's disease.
| العنوان: | Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer's disease. |
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| المؤلفون: | Naderi Yeganeh, Pourya, Kwak, Sang Su, Jorfi, Mehdi, Koler, Katjuša, Kalatturu, Thejesh, von Maydell, Djuna, Liu, Zhiqing, Guo, Kevin, Choi, Younjung, Park, Joseph, Abarca, Nelson, Bakiasi, Grisilda, Cetinbas, Murat, Sadreyev, Ruslan, Griciuc, Ana, Quinti, Luisa, Choi, Se Hoon, Xia, Weiming, Tanzi, Rudolph E, Hide, Winston, Kim, Doo Yeon |
| المصدر: | Neuron ; ISSN:1097-4199 |
| بيانات النشر: | Elsevier Science |
| سنة النشر: | 2024 |
| المجموعة: | PubMed Central (PMC) |
| مصطلحات موضوعية: | 3D human neuronal cell models, Alzheimer’s disease, amyloid beta 42, drug target discovery, integrative analysis, p38 MAP kinase, pathway analysis, phosphoproteomics, tau pathology, transcriptomics |
| الوصف: | Alzheimer's disease (AD) presents a complex pathological landscape, posing challenges to current therapeutic strategies that primarily target amyloid-β (Aβ). Using a novel integrative pathway activity analysis (IPAA), we identified 83 dysregulated pathways common between both post-mortem AD brains and three-dimensional AD cellular models showing robust Aβ42 accumulation. p38 mitogen-activated protein kinase (MAPK) was the most upregulated common pathway. Active p38 MAPK levels increased in the cellular models, human brains, and 5XFAD mice and selectively localized to presynaptic dystrophic neurites. Unbiased phosphoproteomics confirmed increased phosphorylation of p38 MAPK substrates. Downstream activation of MAPK-activated protein kinase 2 (MK2) plays a crucial role in Aβ42-p38 MAPK-mediated tau pathology. Therapeutic targeting of the p38 MAPK-MK2 axis with selective inhibitors significantly reduced Aβ42-driven tau pathology and neuronal loss. IPAA prioritizes the best models to derisk target-drug discovery by integrating human tissue gene expression with functional readouts from cellular models, enabling the identification and validation of high-confidence AD therapeutic targets. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://doi.org/10.1016/j.neuron.2024.10.029; https://pubmed.ncbi.nlm.nih.gov/39610246 |
| DOI: | 10.1016/j.neuron.2024.10.029 |
| الاتاحة: | https://doi.org/10.1016/j.neuron.2024.10.029 https://pubmed.ncbi.nlm.nih.gov/39610246 |
| Rights: | Copyright © 2024 Elsevier Inc. All rights reserved. |
| رقم الانضمام: | edsbas.3FB451C6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.neuron.2024.10.029 |
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