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Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer's disease. | LitMetric

AI Article Synopsis

  • Alzheimer's disease (AD) poses significant treatment challenges, particularly targeting amyloid-β (Aβ), but a new analysis method uncovered 83 dysfunctional pathways relevant to AD in both human brains and lab models.
  • The p38 MAPK pathway was notably upregulated and linked to tau pathology and neuronal damage, highlighting its potential as a therapeutic target.
  • By using integrative pathway activity analysis (IPAA), researchers can combine human data with cellular models to efficiently identify promising drug targets for AD treatment.*

Article 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.

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Source
http://dx.doi.org/10.1016/j.neuron.2024.10.029DOI Listing

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