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Basic Science and Pathogenesis.

Maria de Haro1, Omar El Fadel2, Morgan Catherine Stephens1

  • 1Baylor College of Medicine, Houston, TX, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

Aberrant Hippo pathway activation and mutations are linked to Alzheimer's disease (AD). Targeting this pathway reduces Tau toxicity and levels, offering new therapeutic strategies for AD.

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Genomic and transcriptomic analyses reveal molecular pathway dysregulation in Alzheimer's disease (AD).
  • The Hippo pathway effector YAP1 is dysregulated in AD and aggregates with amyloid.
  • Suppression of Hippo kinase activity shows promise in AD animal models.

Purpose of the Study:

  • To explore the interaction between the Hippo pathway and Tau in Alzheimer's disease pathogenesis.
  • To investigate how Hippo pathway dysregulation contributes to AD.
  • To provide mechanistic insights into targeting the Hippo pathway therapeutically.

Main Methods:

  • Analysis of brain transcriptomes from AD patients and mouse models.
  • Whole-exome sequencing to identify mutations in Hippo pathway genes.
  • In vivo and in vitro assays (behavioral, biochemical, histopathological) to validate Hippo pathway-Tau interactions.

Main Results:

  • Genomic analyses show increased mutations in Hippo pathway genes in AD patients.
  • Transcriptomic data indicate Hippo pathway activation in AD.
  • Hippo pathway modulation suppressed Tau-mediated neuronal dysfunction and reduced Tau levels in fly and human cell models.
  • Tau and YAP1 were found to co-immunoprecipitate.

Conclusions:

  • Aberrant Hippo pathway activation and increased mutations are observed in Alzheimer's disease.
  • Modulating Hippo pathway components effectively reduces Tau toxicity and lowers Tau protein levels.
  • The Hippo pathway represents a potential diagnostic and therapeutic target for AD.