Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor α and the Progression of Alzheimer's Disease

et al. (2013) Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor a and the Progression of Alzheimer's Disease. PLoS ONE 8(11): e80700. doi:10.1371/journal.pone.0080700 Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor a and the Progression of Alzheimer's Disease Teemu Natunen 0 Henna Martiskainen 0 Timo Saraja rvi 0 Seppo Helisalmi 0 Juha-Pekka Pursiheimo 0 Jayashree Viswanathan 0 Marjo Laitinen 0 Petra Ma kinen 0 Tarja Kauppinen 0 Tuomas Rauramaa 0 Ville Leinonen 0 Irina Alafuzoff 0 Annakaisa Haapasalo 0 Hilkka Soininen 0 Mikko Hiltunen 0 Bart Dermaut, Pasteur Institute of Lille, France 0 1 Institute of Clinical Medicine - Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital , Kuopio , Finland , 2 Turku Centre for Biotechnology, University of Turku , Turku , Finland , 3 Department of Pathology, Kuopio University Hospital, Finland and Institute of Clinical Medicine, Unit of Pathology, University of Eastern Finland , Kuopio , Finland , 4 Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital , Kuopio , Finland , 5 Department of Immunology , Genetics and Pathology , Uppsala University , Uppsala , Sweden Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-b (Ab). Activation of liver X receptor a (LXRa) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Ab. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRa 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 e4 allele increased soluble Ab42 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 Ab42 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 LXRa and the levels of soluble Ab42. - Funding: This study was funded by the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, Sigrid Juselius Foundation, the Strategic Funding of the University of Eastern Finland (UEF-Brain), and BIOMARKAPD project in the JPND programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Alzheimers disease (AD), the most common cause of dementia in elderly, is a progressive neurodegenerative disease leading to severe memory impairment and finally to death. The major neuropathological hallmarks are the extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) [1]. Aggregation of amyloid-b (Ab) peptide to Ab oligomers and finally to amyloid plaques has been postulated to trigger downstream events in AD, such as hyperphosphorylation of tau leading to the formation of NFTs, synaptic dysfunction, and loss of neurons in specific brain areas. Ab is processed from amyloid precursor protein (APP) after sequential cleavage by b- and c-secretases [2]. It has been suggested that the elevation of Ab levels in the sporadic AD is due to decreased clearance rather than increased production of Ab [3]. Interestingly, the pathogenesis of the familial form of AD was recently shown to involve not only increased Ab production but also slower Ab clearance rate from the cerebrospinal fluid (CSF), implying that similar mechanisms may in fact underlie both forms of the disease [4]. Several enzymes and pathways are involved in Ab degradation and clearance [5]. Furthermore, the strongest genetic risk factor in sporadic AD, allelic variation in APOE gene has been linked to the clearance of Ab [6]. Apolipoprotein E (ApoE) is the major apolipoprotein in the central nervous system (CNS) and it is produced mainly by astrocytes but also by microglia [7]. ApoE mediates the lipid transport between different tissue and cell types [8]. There are three different isoforms of ApoE, ApoE2, -3 and 4, and these are encoded by APOE alleles e2, e3 and e4, respectively. APOE e4 allele increases the risk of AD and decreases the age of onset as compared to the most common allele e3. In contrast, e2 decreases the risk and delays the age of onset [9]. A recent study using CSF biomarkers and PiB PET imaging showed that Ab accumulation in the human brain corresponded to the APOE genotype in an isoform-dependent manner (e4.e3.e2) [10]. Furthermore, the same study showed that ApoE4 is less efficient in Ab clearance than ApoE3 in a mouse model expressing human ApoE isoforms [10]. Liver X receptor a (LXRa) is a ligand-activated transcription factor, which controls the expression of APOE, ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) and other genes involved lipid homeostasis [11]. LXRa is expressed particularly in the liver, but also in the brain. LXRa forms a heterodimer with retinoid X receptor (RXR) and agonists of both LXRa and RXR have been shown to increase ApoE-dependent Ab clearance in AD mouse models [6,12]. Cholesterol transporters, like ABCA1, increase lipidation of ApoE and this is crucial for the Ab clearance induced by an LXRa agonist [13]. Recently, the RXR agonist bexarotene was shown to reduce soluble Ab levels and amyloid plaque burden as well as to reverse the cognitive deficits in two different AD mouse models after short- and long-term administration of the drug [12]. In spite of the fact that other studies have partially failed to replicate these results [1417], these data emphasize the central role of LXRa and RXR in the regulation of Ab accumulation in AD pathogenesis. We have previously studied the genetic alterations in the NR1H3 gene encoding LXRa in Finnish AD case-control cohort [18]. We found that the single nucleotide polymorphism rs7120118, located in the intron between exons 6 and 7, showed a protective effect for the C allele carriers (OR = 0.70, 95% CI 0.530.93). Moreover, the total-tau and the phospho-tau levels in the CSF were decreased in AD patients carrying the C allele of rs71201 (...truncated)