caa a22 4500 475845889 CHVBK 20180406123914.0 cr unu---uuuuu 170329e20000901xx s 000 0 eng 10.1007/PL00000630 doi (NATIONALLICENCE)springer-10.1007/PL00000630 Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons [Elektronische Daten] [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. Birkhäuser Verlag Basel,, 2000 Key words. Oxidative stress nationallicence mitochondria nationallicence neuritic sprouting nationallicence neurodegeneration nationallicence de la Monte* S. M. Departments of Medicine, aut Neely T. R. Departments of Medicine, aut Cannon J. Departments of Medicine, aut Wands J. R. Departments of Medicine, aut https://doi.org/10.1007/PL00000630 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/PL00000630 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- de la Monte* S. M. Departments of Medicine aut NATIONALLICENCE 700 1- Neely T. R. Departments of Medicine aut NATIONALLICENCE 700 1- Cannon J. Departments of Medicine aut NATIONALLICENCE 700 1- Wands J. R. Departments of Medicine aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer