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

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 neurit ic degeneration cascades in AD. Primary neuron cultures were treated with H 2O2 (9-90 muM) or desferrioxamine (2-25 muM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis a nd 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 retracti on, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal t hread protein and synaptophysin, and reduced distribution of mitochondria i n neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferatio n of neurites, and reduced expression of GAP-43, which has a role in path-f inding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apop tosis due to activation of pro-apoptosis genes, neurite retraction (synapti c 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 requ ired to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.