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A key role for the microglial NADPH oxidase in APP-dependent killing of neurons

Bin Qin1, Laetitia Cartier, Michel Dubois-Dauphin

  • 1Biology of Ageing Laboratory, Department of Geriatrics, Geneva University Hospitals, 2 chemin Petit Bel-Air, 1225 Chêne-Bourg, Geneva, Switzerland.

Neurobiology of Aging
|November 2, 2005
PubMed

Insights

Microglia-generated reactive oxygen species (ROS) contribute to neuronal death in Alzheimer's disease (AD) models. This cell death is linked to amyloid precursor protein (APP) and driven by NADPH oxidase in phagocytes.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Neuronal loss in Alzheimer's disease (AD) is associated with reactive oxygen species (ROS) and amyloid precursor protein (APP) fragments.
  • The precise interplay between APP, ROS, and neuronal death in AD pathogenesis requires further elucidation.

Purpose of the Study:

  • To investigate the role of APP in microglia-mediated ROS generation and subsequent neurotoxicity in a cellular AD model.
  • To determine the specific molecular mechanisms, particularly the involvement of NADPH oxidase, in this process.

Main Methods:

  • Co-culture system using SH-SY5Y neuroblastoma cells overexpressing wild-type (APP-wt) or familial AD mutant (APP-3m) APP with microglia or macrophage cell lines.
  • Assessment of neuronal morphology, growth, cell cycle, and hydrogen peroxide (H2O2) sensitivity.
  • Treatment with ROS-scavengers and NADPH oxidase inhibitor (diphenyleneiodonium chloride, DPI).
  • Utilized macrophage cell lines with and without the NADPH oxidase subunit gp91phox.

Main Results:

  • Overexpression of APP-wt or APP-3m in neuroblastoma cells did not directly induce cell death or alter H2O2 sensitivity.
  • Co-culture with microglia led to ROS generation and neuronal death, which was exacerbated in APP-3m-expressing neurons.
  • Neuroblastoma cell death was reduced by ROS-scavengers and DPI, indicating a role for ROS and NADPH oxidase.
  • Macrophage cell lines mimicked microglial behavior, but gp91phox-deficient macrophages failed to induce neuronal killing.

Conclusions:

  • Amyloid precursor protein (APP) influences microglia activation, leading to reactive oxygen species (ROS) production.
  • Phagocyte NADPH oxidase is a key mediator of ROS generation and subsequent neuronal death in this cellular model of Alzheimer's disease (AD).
  • Targeting NADPH oxidase may offer a therapeutic strategy for mitigating neurodegeneration in AD.

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