title: The alternative splicing of the apolipoprotein E gene is unperturbed in the brains of Alzheimer's disease patients.
abstract: The prevalence of Alzheimer's disease (AD) is increasing rapidly worldwide due to an ageing population and a lack of disease modifying therapeutics. In monogenic forms of AD mutations lead to the accumulation of neurotoxic peptides called beta-amyloid. Beta-amyloid accumulation is also postulated to precipitate sporadic AD although the pathogenesis of this common form remains largely unknown. The two leading risk factors for sporadic AD are ageing and the possession of the APOE epsilon 4 allele. Changes in APOE expression that are independent of the epsilon genotype have also been described in the AD brain including a recent RNA-Seq analysis that showed upregulation of a rare alternative splice isoform (APOE-005). To replicate these RNA-Seq findings we used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) to compare APOE-005 and total APOE expression in the superior temporal gyrus of 14 AD cases and 16 neurologically normal controls. In AD, this area shows prominent beta-amyloid deposition but few neurofibrillary tangles and only moderate neuronal loss. As poorer RNA quality among the AD cases was a likely confounder in this study, the analysis was repeated in a RIN-matched sub-cohort of 17 individuals. Contrary to the original RNA-Seq study, we found no difference in total APOE, APOE-005 or the common isoform, APOE-001, between AD cases and controls. Our findings are consistent with ApoE acting largely at the protein level to increase the risk for sporadic AD.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Mills
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Sheahan
authors.forename: Donna
authors.initials: D
authors.lastname: Lai
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.forename: Michael
authors.initials: M
authors.lastname: Janitz
authors.forename: Greg T
authors.initials: GT
authors.lastname: Sutherland
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020871:RNA Stability; D014158:Transcription, Genetic
chemical_list: D001057:Apolipoproteins E