IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain

Cell Rep. 2016 Oct 18;17(4):941-948. doi: 10.1016/j.celrep.2016.09.075.


Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains.

Keywords: Alzheimer’s disease; Amyloid-β42; STAT6; inflammation; interlukin-4; neural stem cell; neuro-immune crosstalk; neurodegeneration; regeneration; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Cell Plasticity
  • Cell Proliferation
  • Interleukin-4 / metabolism*
  • Microglia
  • Nerve Degeneration / pathology
  • Neural Stem Cells / cytology
  • Neurogenesis*
  • Neurons
  • Peptide Fragments / metabolism*
  • Phenotype
  • Protein Aggregates*
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction*
  • Zebrafish / metabolism


  • Amyloid beta-Peptides
  • Peptide Fragments
  • Protein Aggregates
  • STAT6 Transcription Factor
  • amyloid beta-protein (1-42)
  • Interleukin-4