title: Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease.
abstract: Previous studies have evaluated gene expression in Alzheimer's disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD.
authors.affiliation: Centre for Biostatistics, Bioinformatics and Biomarkers, Plymouth University, Plymouth UK.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Li
authors.affiliation: Centre for Biostatistics, Bioinformatics and Biomarkers, Plymouth University, Plymouth UK.
authors.forename: Jintao
authors.initials: J
authors.lastname: Long
authors.affiliation: Institute of Cardiovascular and Cell Sciences, St. George University, London UK.
authors.forename: Taigang
authors.initials: T
authors.lastname: He
authors.affiliation: School of Biomedicine and Healthcare Sciences, Plymouth University, Plymouth UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Belshaw
authors.affiliation: National Heart and Lung Institute, Imperial College, London UK.
authors.forename: James
authors.initials: J
authors.lastname: Scott
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D020013:Calcium Signaling; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods; D020543:Proteome / Q000378:metabolism*; D018511:Systems Integration
chemical_list: D009419:Nerve Tissue Proteins; D020543:Proteome