RGD Reference Report - Amyloid beta-mediated epigenetic alteration of insulin-like growth factor binding protein 3 controls cell survival in Alzheimer's disease. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

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.
RGD ID: 10402572
Pubmed: PMID:24964199   (View Abstract at PubMed)
PMCID: PMC4070895   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0099047   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOIgfbp3 (Mus musculus)10402572; 10402572mRNA:decreased expression:hippocampusRGD 
Alzheimer's disease  IEP 10402572mRNA:decreased expression:hippocampusRGD 

Objects Annotated

Genes (Rattus norvegicus)
Igfbp3  (insulin-like growth factor binding protein 3)

Genes (Mus musculus)
Igfbp3  (insulin-like growth factor binding protein 3)

Genes (Homo sapiens)
IGFBP3  (insulin like growth factor binding protein 3)


Additional Information