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

Teemu Natunen,Seppo Helisalmi,Petra Mäkinen,Tuomas Rauramaa,Annakaisa Haapasalo,Jayashree Viswanathan,Henna Martiskainen,Tarja Kauppinen,Marjo Laitinen,Juha-Pekka Pursiheimo,Mikko Hiltunen,Timo Sarajärvi,Ville Leinonen,Hilkka Soininen,Irina Alafuzoff

doi:10.1371/journal.pone.0080700

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.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia in elderly, is a progressive neurodegenerative disease leading to severe memory impairment and to death
Before determining the genetic effects of APOE and NR1H3 gene variations in the brain, we first performed biochemical assessment of the brain sample set consisting of inferior temporal cortex samples from 87 subjects with neuropathologically welldefined AD neurofibrillary changes (Table 1)
We have investigated the effects of rs7120118 variation on the expression of NR1H3, APOE, ATP-binding cassette transporter A1 (ABCA1) and ABCG1, the levels of soluble Ab42, and b-secretase activity in a sample set containing inferior temporal cortex samples of neuropathologically examined subjects with AD pathology

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia in elderly, is a progressive neurodegenerative disease leading to severe memory impairment and to death. 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]. The strongest genetic risk factor in sporadic AD, allelic variation in APOE gene has been linked to the clearance of Ab [6]. APOE e4 allele increases the risk of AD and decreases the age of onset as compared to the most common allele e3. 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]. The same study showed that ApoE4 is less efficient in Ab clearance than ApoE3 in a mouse model expressing human ApoE isoforms [10]

Methods

Results

Conclusion