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Drug Development.

Pourya Naderi Yeganeh1,2, Sang Su Kwak2,3, Mehdi Jorfi2,3

  • 1Beth Israel Deaconess Medical Center, Boston, MA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 26, 2025
PubMed
Summary
This summary is machine-generated.

A new bioinformatics platform, Integrative Pathway Activity Analysis (IPAA), accurately predicts Alzheimer's disease (AD) mechanisms relevant to humans. Targeting the p38 MAPK-MK2 pathway in models reduced AD pathology, offering a promising therapeutic strategy.

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Area of Science:

  • Neuroscience
  • Bioinformatics
  • Pharmacology

Background:

  • Alzheimer's disease (AD) treatments successful in preclinical models often fail in human trials.
  • A systematic approach is needed to validate preclinical target mechanisms for human therapeutic relevance.
  • Bridging the preclinical-to-clinical gap is crucial for effective AD drug development.

Purpose of the Study:

  • To develop and validate a bioinformatics platform (IPAA) for assessing preclinical model relevance to human AD.
  • To identify conserved AD pathway dysregulations between human brains and preclinical models.
  • To evaluate the therapeutic potential of targeting identified pathways in AD models.

Main Methods:

  • Developed Integrative Pathway Activity Analysis (IPAA) to map pathway activity from omics data.
  • Assessed mechanistic similarities between AD brain transcriptomes and human AD cellular models.
  • Performed phosphoproteomics and pharmacologically tested key pathways in 3D models.

Main Results:

  • IPAA demonstrated high correlation of pathway dysregulation between AD brain regions (r=0.84).
  • Identified 83 shared dysregulated pathways between AD brains and a 3D model, including p38 MAPK, YAP1/TAZ, E-cadherin, CDC20, and APC/C.
  • Targeting p38 MAPK with Losmapimod significantly reduced AD pathology markers in 3D models and human microglia, highlighting the p38 MAPK-MK2 axis role.

Conclusions:

  • IPAA facilitates rapid preclinical assessment of target pathways for AD pathology.
  • The p38 MAPK-MK2 axis is a critical driver of human AD pathology.
  • This approach enhances confidence in targeting pathways with potential clinical impact for AD.