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 cy tosolic calcium and increased generation of reactive oxygen species (ROS). The beta -amyloid fragment (A beta) of the amyloid precursor protein induce s 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 neuron al excitotoxicity, leading to apoptosis. We examined the possibility that H C may augment A beta neurotoxicity. HG potentiated the A beta -induced incr ease in Cytosolic calcium and apoptosis in differentiated SH-SY-5Y human ne uroblastoma cells. The antioxidant vitamin E and the glutathione precursor N-acetyl-L-cysteine blocked apoptosis following cotreatment with HC and A b eta, indicating that apoptosis is associated with oxidative stress. These f indings underscore that moderate accumulation of excitotoxins at concentrat ions that alone do not appear to initiate adverse events may enhance the ef fects of other factors known to cause neurodegeneration such as A beta.