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Inhibition of histone deacetylation enhances the neurotoxicity induced by the c‐terminal fragments of amyloid precursor protein
Author(s) -
Kim HyeSun,
Kim EunMee,
Kim NaJung,
Chang KeunA,
Choi Yoori,
Ahn KwangWoo,
Lee JunHo,
Kim Seonghan,
Park Cheol Hyoung,
Suh YooHun
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10845
Subject(s) - histone acetyltransferase , acetylation , histone , amyloid precursor protein , sodium butyrate , neurotoxicity , histone deacetylase , histone deacetylase 2 , hdac1 , transcription factor , histone deacetylase 5 , microbiology and biotechnology , sap30 , chemistry , epigenetics , histone deacetylase inhibitor , biology , biochemistry , gene , alzheimer's disease , medicine , disease , organic chemistry , toxicity
Abstract 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. © 2003 Wiley‐Liss, Inc.