Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-25T19:03:03.913Z Has data issue: false hasContentIssue false
  • English
  • Français

CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

Published online by Cambridge University Press:  16 April 2020

Heike Kölsch ,
Dieter Lütjohann ,
Frank Jessen ,
Julius Popp ,
Frank Hentschel ,
Peter Kelemen ,
Sandra Schmitz ,
Wolfgang Maier  and
Reinhard Heun
Heike Kölsch*
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Dieter Lütjohann
Affiliation:
Institute of Clinical Biochemistry and Pharmacology, University of Bonn, Germany
Frank Jessen
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Julius Popp
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Frank Hentschel
Affiliation:
Division of Neuroradiology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany
Peter Kelemen
Affiliation:
Division of Neuroradiology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany
Sandra Schmitz
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Wolfgang Maier
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Reinhard Heun
Affiliation:
Division of Neuroscience, University of Birmingham, UnitedKingdom
*
*Corresponding author. Unikliniken Bonn, Klinik fur Psychiatrie und Psychotherapie, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. Tel.: +49 228 287 19398; fax: +49 228 287 16383. E-mail address: heike.koelsch@ukb.uni-bonn.de (H. Kölsch).
Get access

Abstract

Background

Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.

Methods

We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.

Results

Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).

Conclusion

Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

Keywords

Cholesterol 24S-hydroxylaseAlzheimer’s diseaseCSFCholesterol metabolism
Type
Original article
Information
European Psychiatry , Volume 24 , Issue 3 , April 2009 , pp. 183 - 190
Copyright
Copyright © Elsevier Masson SAS 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Barrett, J.C., Fry, B., Maller, J., Daly, M.J.Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263–265CrossRefGoogle ScholarPubMed
Bogdanovic, N., Bretillon, L., Lund, E.G., Diczfalusy, U., Lannfelt, L., Winblad, B.et al.On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 2001;314:45–48CrossRefGoogle ScholarPubMed
Brown, J. IIITheisler, C., Silberman, S., Magnuson, D., Gottardi-Littell, N., Lee, J.M.et al.Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J Biol Chem 2004;279:34674–34681CrossRefGoogle ScholarPubMed
Cartharius, K., Frech, K., Grote, K., Klocke, B., Haltmeier, M., Klingenhoff, A.et al.MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 2005;21:2933–2942CrossRefGoogle ScholarPubMed
Chalmers, K.A., Culpan, D., Kehoe, P.G., Wilcock, G.K., Hughes, A., Love, S.APOE promoter, ACE1 and CYP46 polymorphisms and beta-amyloid in Alzheimer’s disease. Neurpt 2004;15:95–98Google ScholarPubMed
Dupuy, A.M., Mas, E., Ritchie, K., Descomps, B., Badiou, S., Cristol, J.P.et al.The relationship between apolipoprotein E4 and lipid metabolism is impaired in Alzheimer’s disease. Gerontology 2001;47:213–218CrossRefGoogle ScholarPubMed
Fernandez del Pozo, V., Alvarez Alvarez, M., Fernandez Martinez, M., Galdos Alcelay, L., Gomez Busto, F., Pena, J.A.et al.Polymorphism in the cholesterol 24S-hydroxylase gene (CYP46A1) associated with the APOEpsilon3 allele increases the risk of Alzheimer’s disease and of mild cognitive impairment progressing to Alzheimer’s disease. Dement Geriatr Cogn Disord 2006;21:81–87CrossRefGoogle ScholarPubMed
Folstein, M.F., Folstein, S.E., McHugh, P.R.Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198CrossRefGoogle Scholar
Franke, Y., Peoples, R.J., Francke, U.Identification of GTF2IRD1, a putative transcription factor within the Williams–Beuren syndrome deletion at 7q11.23. Cytogenet Cell Genet 1999;86:296–304CrossRefGoogle ScholarPubMed
Golanska, E., Hulas-Bigoszewska, K., Wojcik, I., Rieske, P., Styczynska, M., Peplonska, B.et al.CYP46: a risk factor for Alzheimer’s disease or a coincidence?. Neurosci Lett 2005;383:105–108CrossRefGoogle ScholarPubMed
Hamajima, N., Saito, T., Matsuo, K., Kozaki, K., Takahashi, T., Tajima, K.Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping. Jpn J Cancer Res 2000;91:865–868CrossRefGoogle ScholarPubMed
Helisalmi, S., Vepsalainen, S., Koivisto, A.M., Mannermaa, A., Iivonen, S., Hiltunen, M.et al.Association of CYP46 intron 2 polymorphism in Finnish Alzheimer’s disease samples and a global scale summary. J Neurol Neurosurg Psychiatr 2006;77:421–422CrossRefGoogle Scholar
Hixson, J.E., Vernier, D.T.Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31:545–548Google ScholarPubMed
Holzapfel, J., Heun, R., Lutjohann, D., Jessen, F., Maier, W., Kolsch, H.PPARD haplotype influences cholesterol metabolism but is no risk factor of Alzheimer’s disease. Neurosci Lett 2006;408:57–61CrossRefGoogle ScholarPubMed
Jeong, J.H., Jin, J.S., Kim, H.N., Kang, S.M., Liu, J.C., Lengner, C.J.et al.Expression of Runx2 transcription factor in non-skeletal tissues, sperm and brain. J Cell Physiol 2008;217:511–517CrossRefGoogle ScholarPubMed
Johansson, A., Katzov, H., Zetterberg, H., Feuk, L., Johansson, B., Bogdanovic, N.et al.Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer’s disease. Hum Genet 2004;114:581–587Google ScholarPubMed
Kivipelto, M., Helkala, E.L., Laakso, M.P., Hanninen, T., Hallikainen, M., Alhainen, K.et al.Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322:1447–1451CrossRefGoogle ScholarPubMed
Kolanczyk, M., Kuhnisch, J., Kossler, N., Osswald, M., Stumpp, S., Thurisch, B.et al.Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin. BMC Med 2008;6:21CrossRefGoogle ScholarPubMed
Kölsch, H., Heun, R., Kerksiek, A., Bergmann, K.V., Maier, W., Lütjohann, D.Altered levels of plasma 24S- and 27-hydroxycholesterol in demented patients. Neurosci Lett 2004;368:303–308CrossRefGoogle ScholarPubMed
Kölsch, H., Lütjohann, D., Ludwig, M., Schulte, A., Ptok, U., Jessen, F.et al.Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol Psychiatry 2002;7:899–902CrossRefGoogle ScholarPubMed
Kölsch, H., Lütjohann, D., Tulke, A., Björkhem, I., Rao, M.L.The neurotoxic effect of 24-hydroxycholesterol on SH-SY5Y human neuroblastoma cells. Brain Res 1999;818:171–175CrossRefGoogle ScholarPubMed
Lander, E.S.The new genomics: global views of biology. Science 1996;274:536–539CrossRefGoogle ScholarPubMed
Lund, E.G., Guileyardo, J.M., Russell, D.W.cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A 1999;96:7238–7243CrossRefGoogle Scholar
Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, A., Diczfalusy, U.et al.Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 1996;93:9799–9804CrossRefGoogle ScholarPubMed
Ma, S.L., Tang, N.L., Lam, L.C., Chiu, H.F.Polymorphisms of the cholesterol 24-hydroxylase (CYP46A1) gene and the risk of Alzheimer’s disease in a Chinese population. Int Psychogeriatr 2006;18:37–45CrossRefGoogle ScholarPubMed
Mauch, D.H., Nagler, K., Schumacher, S., Goritz, C., Muller, E.C., Otto, A.et al.CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001;294:1354–1357CrossRefGoogle ScholarPubMed
Nalla, V.K., Rogan, P.K.Automated splicing mutation analysis by information theory. Hum Mutat 2005;25:334–342CrossRefGoogle ScholarPubMed
Ohyama, Y., Meaney, S., Heverin, M., Ekstrom, L., Brafman, A., Shafir, M.et al.Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): marked insensitivity toward different regulatory axes. J Biol Chem 2006;281:3810–3820CrossRefGoogle ScholarPubMed
Palmer, S.J., Tay, E.S., Santucci, N., Cuc Bach, T.T., Hook, J., Lemckert, F.A.et al.Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development. Gene Expr Patterns 2007;7:396–404CrossRefGoogle ScholarPubMed
Panzenboeck, U., Balazs, Z., Sovic, A., Hrzenjak, A., Levak-Frank, S., Wintersperger, A.et al.ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem 2002;277:42781–42789CrossRefGoogle Scholar
Papassotiropoulos, A., Streffer, J.R., Tsolaki, M., Schmid, S., Thal, D., Nicosia, F.et al.Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 2003;60:29–35CrossRefGoogle ScholarPubMed
Peng, B., Kimmel, M.Simulations provide support for the common disease-common variant hypothesis. Genetics 2007;175:763–776CrossRefGoogle ScholarPubMed
Richardson, J.A., Amantea, C.M., Kianmahd, B., Tetradis, S., Lieberman, J.R., Hahn, T.J.et al.Oxysterol-induced osteoblastic differentiation of pluripotent mesenchymal cells is mediated through a PKC- and PKA-dependent pathway. J Cell Biochem 2007;100:1131–1145CrossRefGoogle ScholarPubMed
Shibata, N., Kawarai, T., Lee, J.H., Lee, H.S., Shibata, E., Sato, C.et al.Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer’s disease. Neurosci Lett 2006;391:142–146CrossRefGoogle Scholar
Strittmatter, W.J., Weisgraber, K.H., Huang, D.Y., Dong, L.-M., Salvesen, G.S., Pericak-Vance, M.et al.Binding of human apolipoprotein E to synthetic amyloid β peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:8098–8102CrossRefGoogle ScholarPubMed
Teunissen, C.E., Lutjohann, D., Von, B.K., Verhey, F., Vreeling, F., Wauters, A.et al.Combination of serum markers related to several mechanisms in Alzheimer’s disease. Neurobiol Aging 2003;24:893–902CrossRefGoogle ScholarPubMed
The International HapMap Consortium A second generation human haplotype map of over 3.1 million SNPs. Nature 2007;449:851–861CrossRefGoogle Scholar
Vevera, J., Fisar, Z., Kvasnicka, T., Zdenek, H., Starkova, L., Ceska, R.et al.Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res 2005;133:197–203CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.