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Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated

C Matrone1, R Marolda, S Ciafrè

  • 1Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy. c.matrone@inmm.cnr.it

Proceedings of the National Academy of Sciences of the United States of America
|June 25, 2009
PubMed

Insights

Increased amyloid-beta (Abeta) production triggers abnormal tyrosine kinase receptor A (TrkA) phosphorylation, activating a death pathway in neurons. Inhibiting this pathway protects against neuronal death, suggesting a novel Alzheimer's disease mechanism.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cellular Signaling

Background:

  • Amyloid-beta (Abeta) production is implicated in Alzheimer's disease pathogenesis.
  • Nerve Growth Factor (NGF) signaling is crucial for neuronal survival and function.
  • Dysregulation of cellular signaling pathways can lead to neurodegeneration.

Purpose of the Study:

  • To investigate the role of NGF signal failure and Abeta production in hippocampal neuron death.
  • To elucidate the signaling pathway linking Abeta production to neuronal apoptosis.
  • To identify potential therapeutic targets for Alzheimer's disease by understanding this mechanism.

Main Methods:

  • Investigated Abeta production and tyrosine kinase receptor A (TrkA) phosphorylation in hippocampal neurons.
  • Analyzed the activation of the phospholipase C gamma (PLCgamma) pathway.
  • Utilized pharmacologic inhibition and receptor silencing (TrkA, p75) to assess neuroprotection.
  • Performed coimmunoprecipitation to study protein interactions (TrkA, p75, Abeta, PS1).

Main Results:

  • Increased Abeta production due to NGF signal failure induced abnormal TrkA phosphorylation.
  • This phosphorylation activated the PLCgamma pathway, leading to neuronal death.
  • Inhibition of TrkA phosphorylation and silencing of TrkA/p75 receptors prevented PLCgamma activation and protected neurons.
  • TrkA, p75, Abeta, and PS1 were found to coimmunoprecipitate, indicating direct interplay.

Conclusions:

  • A cellular mechanism exists where a trophic signaling system can switch to a death-inducing pathway.
  • This pathway involves Abeta production, TrkA phosphorylation, PLCgamma activation, and p75 processing.
  • Targeting TrkA phosphorylation and TrkA/p75 receptors offers a potential therapeutic strategy for Alzheimer's disease.

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