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Neuron, November 27, 2024 | https://doi.org/10.1016/j.neuron.2024.10.029
Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer’s disease
Pourya Naderi Yeganeh,1,11 Sang Su Kwak,2,3,11 Mehdi Jorfi,2,3 Katjusa Koler,4 Thejesh Kalatturu,2,3 Djuna von Maydell,2,5 Zhiqing Liu,6 Kevin Guo,7 Younjung Choi,2 Joseph Park,2,3 Nelson Abarca,2,3 Grisilda Bakiasi,2,3 Murat Cetinbas,8 Ruslan Sadreyev,8 Ana Griciuc,2,3 Luisa Quinti,2,3 Se Hoon Choi,2,3 Weiming Xia,6,9,10 Rudolph E. Tanzi,2,3,* Winston Hide,1,4,* and Doo Yeon Kim2,3,12,*
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
3McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA
4Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, UK
5Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
6Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
7Avice Laboratories, Acton, MA, USA
8Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
9Geriatric Research Education and Clinical Center, Bedford VA Healthcare System, Bedford, MA, USA
10Department of Biological Sciences, University of Massachusetts Kennedy College of Science, Lowell, MA, USA
11These authors contributed equally
12Lead contact
*Correspondence: R.E.T., W.H., D.Y.K.
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
3McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA
4Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, UK
5Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
6Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
7Avice Laboratories, Acton, MA, USA
8Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
9Geriatric Research Education and Clinical Center, Bedford VA Healthcare System, Bedford, MA, USA
10Department of Biological Sciences, University of Massachusetts Kennedy College of Science, Lowell, MA, USA
11These authors contributed equally
12Lead contact
*Correspondence: R.E.T., W.H., D.Y.K.
Abstract
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.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-28)
- 국외 연구진
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