Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease
dc.contributor.author | khazaeli, Shahab | |
dc.contributor.author | Long, J | |
dc.contributor.author | He, T | |
dc.contributor.author | Belshaw, Robert | |
dc.contributor.author | Scott, J | |
dc.date.accessioned | 2015-11-26T09:01:23Z | |
dc.date.available | 2015-11-26T09:01:23Z | |
dc.date.issued | 2015-12 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.other | 12393 | |
dc.identifier.uri | http://hdl.handle.net/10026.1/3833 | |
dc.description.abstract |
<jats:title>Abstract</jats:title><jats:p>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.</jats:p> | |
dc.format.extent | 0-0 | |
dc.format.medium | Electronic | |
dc.language | en | |
dc.language.iso | en | |
dc.publisher | Springer Science and Business Media LLC | |
dc.subject | Alzheimer Disease | |
dc.subject | Brain | |
dc.subject | Calcium Signaling | |
dc.subject | Gene Expression Profiling | |
dc.subject | Gene Expression Regulation | |
dc.subject | Genomics | |
dc.subject | Humans | |
dc.subject | Nerve Tissue Proteins | |
dc.subject | Protein Interaction Mapping | |
dc.subject | Proteome | |
dc.subject | Systems Integration | |
dc.title | Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Meta-Analysis | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000358360500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.issue | 0 | |
plymouth.volume | 5 | |
plymouth.publication-status | Published online | |
plymouth.journal | Scientific Reports | |
dc.identifier.doi | 10.1038/srep12393 | |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/Faculty of Health | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/Research Groups | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED) | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBBB | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR | |
plymouth.organisational-group | /Plymouth/Users by role | |
dc.publisher.place | England | |
dcterms.dateAccepted | 2015-06-15 | |
dc.identifier.eissn | 2045-2322 | |
dc.rights.embargoperiod | Not known | |
rioxxterms.versionofrecord | 10.1038/srep12393 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2015-12 | |
rioxxterms.type | Journal Article/Review |