These observations provide a platform for structural modifications of efavirenz to modulate CYP46A1 activity as a therapeutic target of brain disorders such as Alzheimer's disease, for which currently no treatment is available.
The modulation of CYP46A1 activity by genetic and pharmacologic means is also presented along with a brief synopsis of the two clinical trials that evaluate CYP46A1 as a therapeutic target for Alzheimer's disease as well as Dravet and Lennox-Gastaut syndromes.
However, AD patients with the CYP46A1 TT, but not CC, genotype had higher 24-OHC levels, which indicated that there may be other mechanisms in the relationship between CYP46A1 polymorphisms and AD.
The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1.
Our results showed that no significant associations between CYP46A1rs4900442 genetic polymorphism and risk of AD in allele model T vs. C (OR=0.947, 95%CI=0.853-1.051), dominant model CC+TC vs. TT (OR=0.878, 95%CI=0.734-1.049) and recessive model CC vs. TC+TT (OR=0.974, 95%CI=0.826-1.149).
In conclusion, our meta-analysis has successfully proved that CC genotype of the CYP46A1 T/C polymorphism could increase the risk of AD, and this effect would be weakened in APOE ε4 non-carriers and strengthened in APOE ε4 carriers.
Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces Abeta pathology in mouse models of AD.
We previously found that the polymorphisms of cholesterol 24-hydroxylase (CYP46A1) gene were associated with the risk of Alzheimer's disease (AD) in Chinese.
The aim of this review is to describe and summarize the findings of the researches about the relationship between CYP46 and AD that have been published in the past 9 years.
A single-nucleotide polymorphism (SNP) in the CYP46A1 gene, designated as rs754203 and associated with Alzheimer disease, was evaluated as a genetic risk factor for primary open-angle glaucoma (POAG), as well as plasma 24S-hydroxycholesterol levels.
Logistic regression analysis showed that the highest risk for AD was found for individuals who co-inherited APOE epsilon4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46rs754203 g allele.
One reason may be the previously demonstrated abnormal expression of cholesterol 24S-hydroxylase in astrocytes in AD, which may limit the usefulness of this plasma marker in this specific disease.
The purpose of this case-control study was to determine whether single nucleotide polymorphisms (SNPs) A-->G in the intron 2 of CYP46 gene and G-->A (R219K) in the exon 7 of ABCA1 gene are associated with sporadic AD in the Chinese Han population.
Based on the results of genome-wide screens, along with biological studies, we selected three genes as candidates for AD risk factors: ATP-binding cassette transporter A1 (ABCA1), cholesterol 25-hydroxylase (CH25H) and cholesterol 24-hydroxylase (CH24H).