Homocysteine Potentiates B-Amyloid Neurotoxicity: Role of Oxidative Stress
Pei I. Ho, Scott C. Collins, Sirikarnt Dhitavat, Daniela Ortiz, David Ashline, Eugene Rogers and Thomas B. Shea
Journal of Neurochemistry. 2001; 78:1-6.
The cause of neuronal degeneration in Alzheimer's disease (AD) has not been completely clarifed, but has been variously attributed to increases in cytosolic calcium and increased generation of reactive oxygen species (ROS). The b-amyloid fragment (Ab) 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 Ab neurotoxicity. HC potentiated the Ab-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 Ab, 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 Ab.
Keywords: Alzheimer's disease, apoptosis, b-amyloid, calcium influx, homocysteine, oxidative stress.