Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.
Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD.
Lovell
M A
MA
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Xie
C
C
Markesbery
W R
WR
D000171:Acrolein / Q000378:metabolism / Q000633:toxicity*; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats
D018698:Glutamic Acid; D000171:Acrolein; D005947:Glucose