ArticleNeuron2025
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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Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13citing papers in PubMed
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Who cites it
13 citing papers in PubMed.
- Inhibition of p38α MAPK increases short-term astrocyte reactivity: the exploratory VIP trial in early Alzheimer's disease.Journal of neuroinflammation · 2025Trial
- Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction.Journal of medicinal chemistry · 2026Article
- Human Stem Cell-Derived Models of the Alzheimer's Disease Neuroimmune System.International journal of molecular sciences · 2026Review
- Article
- Aloe-emodin inhibits p38 MAPK pathway in Alzheimer's disease treatment: a network pharmacology and experimental verification.Journal of molecular histology · 2026Article
- CSF proteomic profiling with amyloid and tau pathology identifies distinctive sex-specific alteration of multiple proteins involved in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Non-Catalytic Inhibitors of the p38/MK2 Interface: Repurposing Approved Drugs to Target Neuroinflammation in Alzheimer's Disease.Journal of medicinal chemistry · 2025Article
- Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy.EMBO molecular medicine · 2025Article
- Neuroprotective effects of Yangming-Kaixin-Yizhi formula in Alzheimer's disease: dual regulation of PI3K/Akt and p38 MAPK signaling via network pharmacology and experimental approaches.Metabolic brain disease · 2025Article
- Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease.Science translational medicine · 2025Article
- CD2AP at the junction of nephropathy and Alzheimer's disease.Molecular neurodegeneration · 2025Review
- Scorpion Venom Heat-Resistant Synthetic Peptide Alleviates Neuronal Necroptosis in Alzheimer's Disease Model by Regulating Lnc Gm6410 Under PMInternational journal of molecular sciences · 2025Article
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Authors and funding
21 authors.
Pourya Naderi YeganehDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Sang Su KwakGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Mehdi JorfiGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Katjuša KolerSheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, UK.
Thejesh KalatturuGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Djuna von MaydellGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Zhiqing LiuDepartment of Pharmacology, Physiology and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Kevin GuoAvice Laboratories, Acton, MA, USA.
Younjung ChoiGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Joseph ParkGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Nelson AbarcaGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Grisilda BakiasiGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Murat CetinbasDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Ruslan SadreyevDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Ana GriciucGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Luisa QuintiGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Se Hoon ChoiGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Weiming XiaDepartment of Pharmacology, Physiology and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Geriatric Research Education and Clinical Center, Bedford VA Healthcare System, Bedford, MA, USA; Department of Biological Sciences, University of Massachusetts Kennedy College of Science, Lowell, MA, USA.
Rudolph E TanziGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: tanzi@helix.mgh.harvard.edu.
Winston HideDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, UK. Electronic address: whide@bidmc.harvard.edu.
Doo Yeon KimGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dkim@helix.mgh.harvard.edu.
Funding
TRANSGENICS AND PRESENILIN FUNCTIONP01AG015379 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI BEREZOVSKA, OKSANA · 1998 to 2023
$51.3MROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Elizabeth Austen Lawson, Takara Leah Stanley · 1994 to 2026
$31.6MResilience/Resistance to Alzheimer's Disease in Centenarians and Offspring (RADCO)U19AG073172 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI ANDERSEN, STACY, BOOKHEIMER, SUSAN Y · 2021 to 2025
$23.1MIdentification and Characterization of Novel AD GenesR37MH060009 · NIMH · MASSACHUSETTS GENERAL HOSPITAL · PI TANZI, RUDOLPH EMILE · 2003 to 2012
$7.6MRole of the g-secretase/PS1 complex in APP processingR01AG014713 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI KIM, DOO YEON · 1997 to 2018
$5.9MBig data and small molecules for Alzheimer's diseaseR01AG063913 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI Weiming Xia · 2024 to 2026
$4.1MSystematic modeling and prediction of cell-type-specific and spatiotemporal crosstalk pathways in Alzheimer's DiseaseR01AG071496 · NIA · METHODIST HOSPITAL RESEARCH INSTITUTE · PI KIM, DOO YEON, WONG, STEPHEN TC · 2021 to 2025
$4.0MThe impact of AD-associated genetic variants in 3D human mixed neural-glial models of ADR01AG061891 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI KIM, DOO YEON, TANZI, RUDOLPH EMILE · 2019 to 2023
$3.8MNon-coding RNAs in resilience to Alzheimer’s DiseaseR01AG082093 · NIA · BETH ISRAEL DEACONESS MEDICAL CENTER · PI Winston Alexander Hide, Doo Yeon Kim · 2023 to 2026
$3.4MThe Alzheimer's Disease Resiliome: Pathway Analysis and Drug Discovery.R01AG062547 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI HIDE, WINSTON ALEXANDER, KIM, DOO YEON · 2019 to 2023
$3.3MBig data and small molecules for Alzheimer's diseaseRF1AG063913 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI GOLDSTEIN, LEE E., XIA, WEIMING · 2019 to 2021
$2.9MA novel human 3D neural cell culture system for the characterization of AD genesRF1AG048080 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI KIM, DOO YEON, TANZI, RUDOLPH EMILE · 2014 to 2014
$2.1MBLRD VA I01 BX004730NIA NIH HHS P01 AG015379NIA NIH HHS R01 AG014713NIA NIH HHS R01 AG061891NIA NIH HHS R01 AG062547NIA NIH HHS R01 AG063913NIA NIH HHS R01 AG071496NIA NIH HHS R01 AG072654NIA NIH HHS R01 AG082093NIA NIH HHS R01 AG082328NIA NIH HHS R13 AG026970NIA NIH HHS RF1 AG048080NIA NIH HHS RF1 AG063913NIA NIH HHS U19 AG073172NIDDK NIH HHS P30 DK040561NIMH NIH HHS R37 MH060009
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.
Indexed as
Alzheimer DiseaseIntracellular Signaling Peptides and Proteinsp38 Mitogen-Activated Protein KinasesProtein Serine-Threonine KinasesAmyloid beta-PeptidesAnimalsBrainHumansMaleMAP-Kinase-Activated Kinase 2MiceMice, TransgenicPeptide Fragmentstau ProteinsAmyloid beta-Peptidesamyloid beta-protein (1-42)Intracellular Signaling Peptides and ProteinsMAP-Kinase-Activated Kinase 2p38 Mitogen-Activated Protein KinasesPeptide FragmentsProtein Serine-Threonine Kinasestau Proteins3D human neuronal cell modelsAlzheimer’s diseaseamyloid beta 42drug target discoveryintegrative analysisp38 MAP kinasepathway analysisphosphoproteomicstau pathologytranscriptomics
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