title: Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea.
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Na-Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Keun-A
authors.initials: KA
authors.lastname: Chang
authors.forename: Yoori
authors.initials: Y
authors.lastname: Choi
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Ahn
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Seonghan
authors.initials: S
authors.lastname: Kim
authors.forename: Cheol Hyoung
authors.initials: CH
authors.lastname: Park
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
mesh_terms: D000107:Acetylation / Q000187:drug effects; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002087:Butyrates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015394:Molecular Structure; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D002087:Butyrates; D004791:Enzyme Inhibitors; D006657:Histones; D007211:Indoles; C007293:DAPI; D020932:Nerve Growth Factor; D007770:L-Lactate Dehydrogenase