Changes in functional pathways and hub-gene subnetworks derived from differential co-expression gene pairs in normal brain aging and region-specific Alzheimer's disease

Autor: Yi-Yun Peng, 彭伊筠
Rok vydání: 2016
Druh dokumentu: 學位論文 ; thesis
Popis: 104
Alzheimer's disease (AD) is one of most prevalent progressive neurodegenerative disease. It is believed that main pathology of AD in brain is due to accumulated neuronal plaque and tangle formations. Previous studies indicated that abnormally in the genes APP, PSEN1, PSEN2, and APOE are high risk factors to AD. Recent reports have also suggested that infec-tions from foreign pathogens may cause AD. In spite of much research efforts the underlying pathophysiology of AD remains unclear. Here, our goal is to gain insight into possible new genetic causes of normal brain aging (AG) and brain region-specific AD, Also, to identify changes in functional pathways associated with AG and region-specific AD, and to elaborate on the heterogeneity of AD in five brain regions. The data we use for our study six sets of publically available microarray dataset: one set from brains tissues of people of a wide range of ages not known to have AD or similar brain disorders, and five sets from tissues of five brain regions – entorhinal cortex, hippocampus, medial temporal gyrus, posterior cingulate, and superior frontal gyrus – of AD patients and controls. We use the method of differential co-expression (DCE) analysis for our study. We identified pairs of genes whose correlation of expression levels in control versus test data in-creased significantly (gain of co-expression, or GOC), and those whose correlation decreased significantly (loss of co-expression, or LOC), integrated all the genes involved in GOC and LOC pairs with protein-protein interaction data to construct six core protein-protein interac-tion networks (cPPINs), one for each set of data, and used the networks for hub-gene identifi-cation (high-degree genes in cPPIN) and for pathway studies. There was significant difference between the AG cPPIN and the AD cPPINs, and among regional AD cPPINs. The number of GOC genes greater than LOC genes in the AG cPPIN, but the GOC to LOC ratio is highly region-dependent in the AD networks. Many of hub-genes in the AD cPPINs were also known AD target genes, including TUBB, GAPDH, NEFL, and AMPH. Similarly, many of hub-genes in the AG cPPIN were known AG target genes, including YWHAZ, HSPAB, EEF2, and HIF1A. YWHAZ and XRCC6 were among gene that were AG as well as AD hub-genes and were both AD and AG known target genes. Classes of enriched pathways differed between AG and AD, and intra-regionally in AD. For instance, cancer pathways were seen to be highly enriched in AG, and PC/AD, but absent in HC/AD. Most pathways were either GOC or LOC enriched, but some, including pro-teasome and E. coli related pathways, were both GOC and LOC enriched.
Databáze: Networked Digital Library of Theses & Dissertations
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