Publication Date:
2013-07-26
Description:
Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E epsilon4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rhinn, Herve -- Fujita, Ryousuke -- Qiang, Liang -- Cheng, Rong -- Lee, Joseph H -- Abeliovich, Asa -- K01 AG030514/AG/NIA NIH HHS/ -- P30 AG010129/AG/NIA NIH HHS/ -- R01 MH084995/MH/NIMH NIH HHS/ -- R01AG042317/AG/NIA NIH HHS/ -- R01NS064433/NS/NINDS NIH HHS/ -- R37 AG015473/AG/NIA NIH HHS/ -- U01 AG024904/AG/NIA NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Aug 1;500(7460):45-50. doi: 10.1038/nature12415. Epub 2013 Jul 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23883936" target="_blank"〉PubMed〈/a〉
Keywords:
Age of Onset
;
Aged
;
Alleles
;
Alzheimer Disease/epidemiology/*genetics
;
Amyloid beta-Protein Precursor/metabolism
;
Apolipoprotein E4/*genetics
;
Brain/drug effects/metabolism
;
Cells, Cultured
;
Cerebral Cortex/metabolism
;
Endocytosis
;
Epistasis, Genetic
;
Female
;
Fibroblasts
;
Gene Expression Profiling
;
Genome, Human/*genetics
;
Genome-Wide Association Study
;
*Genomics
;
Heterozygote
;
Humans
;
Membrane Glycoproteins/antagonists & inhibitors/genetics/metabolism
;
Nerve Tissue Proteins/antagonists & inhibitors/genetics/metabolism
;
Neurons/drug effects/metabolism
;
Phenotype
;
Piracetam/analogs & derivatives/pharmacology
;
Polymorphism, Genetic/genetics
;
Proteolysis/drug effects
;
Transcriptome/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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