Cellular and Molecular Life Sciences CMLS

, Volume 57, Issue 10, pp 1471–1481 | Cite as

Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons

  • S. M. de la Monte*
  • T. R. Neely
  • J. Cannon
  • J. R. Wands

Abstract.

Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated with H2O2 (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin, and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection), and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast, hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.

Key words. Oxidative stress; mitochondria; neuritic sprouting; neurodegeneration. 

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Copyright information

© Birkhäuser Verlag Basel, 2000

Authors and Affiliations

  • S. M. de la Monte*
    • 1
  • T. R. Neely
    • 1
  • J. Cannon
    • 1
  • J. R. Wands
    • 1
  1. 1.Departments of Medicine,

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