Amyloid Beta-Mediated Epigenetic Alteration of Insulin-Like Growth Factor Binding Protein 3 Controls Cell Survival in Alzheimer%26apos;s Disease

作者：Sung Hye Youn; Choi Eun Nam; Lyu Dahyun; Mook Jung Inhee; Ahn Jung Hyuck^*

来源：PLos One, 2014, 9(6): e99047.

DOI：10.1371/journal.pone.0099047

Swedish double mutation (KM670/671NL) of amyloid precursor protein (APP) is reported to increase toxic amyloid b (Ab) production via aberrant cleavage at the beta-secretase site and thereby cause early-onset Alzheimer%26apos;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 (H4sw) 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 A beta(1-42)-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 A beta(1-42) toxicity. These data implicate a protective role for IGFBP3 against A beta(1-42)-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-29-deoxycytidine restored IGFBP3 expression at both the mRNA and protein levels. Chronic exposure to A beta(1-42) induced IGFBP3 hypermethylation at CpGs, particularly at loci 2164 and 2173, 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.

• 出版日期2014-6-25