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

• Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-beta (A beta). Activation of liver X receptor alpha (LXR alpha) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of A beta. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXR alpha 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 epsilon 4 allele increased soluble A beta 42 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 A beta 42 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 LXR alpha and the levels of soluble A beta 42.

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