Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer’s disease (original) (raw)

Among the genetic factors known to increase the risk of late onset Alzheimer's diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer's disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer's disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer's disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer's disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer's disease. Alzheimer's disease (AD) is the most common cause of dementia, characterized clinically by a decline in cognitive function and by distinctive brain pathology with neuronal loss and the formation of amyloid plaques and neurofibrillary tangles. Early onset AD is rare and is caused by mutations in specific genes such as amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Late onset AD is the most common form but, although several putative susceptibility genes have been reported, APOE, coding for the Apolipoprotein E, is the most robust susceptibility gene known to date. Three common isoforms of APOE have been recognized: APOE2 (cys112, cys158), APOE3 (cys112, arg158) and APOE4 (arg112, arg158) and the presence of the alleles coding for the APOE4 isoform are associated with an increased risk (up to tenfold in homozygous cases 1) of late onset AD when compared to the most common APOE3 allele or APOE2, a rarer allele, that appears to have, instead, a protective effect 2,3. APOE is a multifunctional glycosylated protein with a major role in lipid transport and atherosclerosis pathogenesis and it is expressed in several organs, with the highest expression in the liver and brain. In the central nervous system, although neurons can produce APOE under certain conditions, non-neuronal cells, mainly astrocytes and to some extent microglia, are the major cell types that express APOE in the brain 4,5. Numerous mechanisms by which APOE influences AD pathogenesis have been proposed, including a role in the clearance of Amyloid β 6,7 , but how this influences the pathogenic molecular processes remains to be clarified.