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Kim, H.S. et al.

Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein.

The AICD (APP intracellular Domain) and C31, caspase- cleaved C-terminal fragment of APP, have been found in Alzheimer's disease (AD) patients' brains and have been reported to induce apoptosis in neuronal cells. In recent, the C-terminal fragments of amyloid precursor protein (APP-CTs) have been reported to form a complex with Fe65 and the histone acetyltransferase Tip60 and are thought to be involved in gene transcription. In this study, based on the hypothesis that APP-CTs might exert neurotoxicity by inducing some gene transcription, we investigated the effects of APP-CTs on histone acetylation which indicates that transcription is actively going on and also on the relationship between histone acetylation and the cytotoxicity induced by APP-CTs in nerve growth factor (NGF)-differentiated PC12 cells and rat primary cortical neurons. Here we demonstrate that the expression of APP-CTs [C31, AICD (C59) and C99] induces increases in acetylation of histone 3 and histone 4 and that treatment with sodium butyrate, an inhibitor of histone deacetylase, significantly enhances the cytotoxicity induced by APP-CTs. The acetylation of histone plays an important role in allowing regulatory proteins to access DNA and is likely to be a major factor in the regulation of gene transcription. Taken together, our results suggest that APP-CTs exert neurotoxicity by transcription-dependent mechanisms and this might contribute to the pathogenesis of AD.[1]

References

Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein. Kim, H.S., Kim, E.M., Kim, N.J., Chang, K.A., Choi, Y., Ahn, K.W., Lee, J.H., Kim, S., Park, C.H., Suh, Y.H. J. Neurosci. Res. (2004) [Pubmed]

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