Generation of reactive oxygen species and activation of NF-κB by non-Aβ component of Alzheimer's disease amyloid
Article first published online: 3 JUL 2002
Journal of Neurochemistry
Volume 82, Issue 2, pages 305–315, July 2002
How to Cite
Tanaka, S., Takehashi, M., Matoh, N., Iida, S., Suzuki, T., Futaki, S., Hamada, H., Masliah, E., Sugiura, Y. and Ueda, K. (2002), Generation of reactive oxygen species and activation of NF-κB by non-Aβ component of Alzheimer's disease amyloid. Journal of Neurochemistry, 82: 305–315. doi: 10.1046/j.1471-4159.2002.00958.x
- Issue published online: 3 JUL 2002
- Article first published online: 3 JUL 2002
- Received December 21, 2001; revised manuscript received March 31, 2002; accepted April 4, 2002.
Non-amyloid beta (Aβ) component of Alzheimer's disease (AD) amyloid (NAC) coexists with Aβ protein in senile plaques. After exposure to NAC fibrils, cortical neurons of rat brain primary culture became apoptotic, while astrocytes were activated with extension of their processes. NAC fibrils decreased the activity of reducing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in cortical neurons more markedly (IC50 = 5.6 µm) than in astrocytes (IC50≈ 50 µm). The neuron-specific toxicity of NAC fibrils was indicated also by an increased release of lactate dehydrogenase from the cells. Neuronal apoptosis was suppressed by pre-treatment with the antioxidants, propyl gallate (PG) and N-t-butyl-phenylnitrone (BPN), or overexpression of human Bcl-2. Exposure to NAC fibrils enhanced generation of reactive oxygen species (ROS) in neurons and less efficiently in astrocytes, as demonstrated by oxidation of 2′,7′-dichlorofluorescin. The site of ROS generation was shown to be mitochondria by oxidation of chloromethyl-tetramethyl rosamine. Exposure to NAC fibrils increased also the nuclear translocation of nuclear factor kappa B (NF-κB) and enhanced its DNA-binding activity, which was inhibited by PG and BPN more efficiently in neurons than in astrocytes. These results suggest that NAC fibrils increase mitochondrial ROS generation and activate NF-κB, thereby causing a differential change in gene expression between neurons and astrocytes in the AD brain.