title: Effects of NR1H3 genetic variation on the expression of liver X receptor α and the progression of Alzheimer's disease.
abstract: Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Aβ. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRα reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ε4 allele increased soluble Aβ42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble Aβ42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXRα and the levels of soluble Aβ42.
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.forename: Henna
authors.initials: H
authors.lastname: Martiskainen
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.forename: Jayashree
authors.initials: J
authors.lastname: Viswanathan
authors.forename: Marjo
authors.initials: M
authors.lastname: Laitinen
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.forename: Tarja
authors.initials: T
authors.lastname: Kauppinen
authors.forename: Tuomas
authors.initials: T
authors.lastname: Rauramaa
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D003710:Demography; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases