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Amyloid beta-mediated epigenetic alteration of insulin-like growth factor binding protein 3 controls cell survival in Alzheimer's disease.

Authors: Sung, HY  Choi, EN  Lyu, D  Mook-Jung, I  Ahn, JH 
Citation: Sung HY, etal., PLoS One. 2014 Jun 25;9(6):e99047. doi: 10.1371/journal.pone.0099047. eCollection 2014.
Pubmed: (View Article at PubMed) PMID:24964199
DOI: Full-text: DOI:10.1371/journal.pone.0099047

Swedish double mutation (KM670/671NL) of amyloid precursor protein (APP) is reported to increase toxic amyloid beta (Abeta) production via aberrant cleavage at the beta-secretase site and thereby cause early-onset Alzheimer's disease (AD). However, the underlying molecular mechanisms leading to AD pathogenesis remains largely unknown. Previously, our transcriptome sequence analyses revealed global expressional modifications of over 600 genes in APP-Swedish mutant-expressing H4 (H4-sw) cells compared to wild type H4 cells. Insulin-like growth factor binding protein 3 (IGFBP3) is one gene that showed significantly decreased mRNA expression in H4-sw cells. In this study, we investigated the functional role of IGFBP3 in AD pathogenesis and elucidated the mechanisms regulating its expression. We observed decreased IGFBP3 expression in the H4-sw cell line as well as the hippocampus of AD model transgenic mice. Treatment with exogenous IGFBP3 protein inhibited Abeta1-42- induced cell death and caspase-3 activity, whereas siRNA-mediated suppression of IGFBP3 expression induced cell death and caspase-3 cleavage. In primary hippocampal neurons, administration of IGFBP3 protein blocked apoptotic cell death due to Abeta1-42 toxicity. These data implicate a protective role for IGFBP3 against Abeta1-42-mediated apoptosis. Next, we investigated the regulatory mechanisms of IGFBP3 expression in AD pathogenesis. We observed abnormal IGFBP3 hypermethylation within the promoter CpG island in H4-sw cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored IGFBP3 expression at both the mRNA and protein levels. Chronic exposure to Abeta1-42 induced IGFBP3 hypermethylation at CpGs, particularly at loci -164 and -173, and subsequently suppressed IGFBP3 expression. Therefore, we demonstrate that expression of anti-apoptotic IGFBP3 is regulated by epigenetic DNA methylation, suggesting a mechanism that contributes to AD pathogenesis.

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CRRD Object Information
CRRD ID: 10402572
Created: 2015-10-27
Species: All species
Last Modified: 2015-10-27
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.