Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress.
The cause of neuronal degeneration in Alzheimer's disease (AD) has not been completely clarified, but has been variously attributed to increases in cytosolic calcium and increased generation of reactive oxygen species (ROS). The beta-amyloid fragment (Abeta) of the amyloid precursor protein induces calcium influx, ROS and apoptosis. Homocysteine (HC), a neurotoxic amino acid that accumulates in neurological disorders including AD, also induces calcium influx and oxidative stress, which has been shown to enhance neuronal excitotoxicity, leading to apoptosis. We examined the possibility that HC may augment Abeta neurotoxicity. HC potentiated the Abeta-induced increase in cytosolic calcium and apoptosis in differentiated SH-SY-5Y human neuroblastoma cells. The antioxidant vitamin E and the glutathione precursor N-acetyl-L-cysteine blocked apoptosis following cotreatment with HC and Abeta, indicating that apoptosis is associated with oxidative stress. These findings underscore that moderate accumulation of excitotoxins at concentrations that alone do not appear to initiate adverse events may enhance the effects of other factors known to cause neurodegeneration such as Abeta.
Ho
P I
PI
Center for Cellular Neurobiology and Neurodegeneration Research and Department of Biochemistry, University of Massachusetts-Lowell, Lowell, Massachusetts 01854, USA.
Collins
S C
SC
Dhitavat
S
S
Ortiz
D
D
Ashline
D
D
Rogers
E
E
Shea
T B
TB
D000111:Acetylcysteine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D003600:Cytosol / Q000378:metabolism; D004357:Drug Synergism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D009447:Neuroblastoma; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D010718:Phosphatidylserines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D009498:Neurotoxins; D010446:Peptide Fragments; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); D006710:Homocysteine; D014810:Vitamin E; D002118:Calcium; D000111:Acetylcysteine