Cholesterol 25-Hydroxylase on Chromosome 10q Is a Susceptibility Gene for Sporadic Alzheimer's Disease

被引：57

作者：

Papassotiropoulos, Andreas ^{[1
]}

Lambert, Jean-Charles ^{[4
]}

Wavrant-De Vrieze, Fabienne ^{[5
]}

Wollmer, M. Axel ^{[1
]}

von der Kammer, Heinz ^{[7
]}

Streffer, Johannes R. ^{[1
]}

Maddalena, Alessia ^{[1
]}

Huynh, Kim-Dung ^{[1
]}

Wolleb, Sibylle ^{[1
]}

Luetjohann, Dieter ^{[8
]}

Schneider, Brigitte ^{[8
]}

Thal, Dietmar R. ^{[9
]}

Grimaldi, Luigi M. E. ^{[11
]}

Tsolaki, Magdalini ^{[12
]}

Kapaki, Elisabeth ^{[13
]}

Ravid, Rivka ^{[14
]}

Konietzko, Uwe ^{[1
]}

Hegi, Thomas ^{[2
]}

Pasch, Thomas ^{[2
]}

Jung, Hans ^{[3
]}

Braak, Heiko ^{[10
]}

Amouyel, Philippe ^{[4
]}

Rogaev, Evgeny I. ^{[6
]}

Hardy, John ^{[5
]}

Hock, Christoph ^{[1
]}

Nitsch, Roger M. ^{[1
]}

机构：

[1] Univ Zurich, Div Psychiat Res, CH-8029 Zurich, Switzerland

[2] Univ Zurich, Inst Anesthesiol, CH-8029 Zurich, Switzerland

[3] Univ Zurich, Dept Neurol, CH-8029 Zurich, Switzerland

[4] Inst Pasteur, INSERM, U508, F-59019 Lille, France

[5] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[6] Univ Massachusetts, Sch Med, Dept Psychiat, Brudnick Neuropsychiat Res Inst, Worcester, MA 01655 USA

[7] Evotec Neurosci, Hamburg, Germany

[8] Univ Bonn, Inst Clin Pharmacol, Bonn, Germany

[9] Univ Bonn, Med Ctr, Inst Neuropathol, Bonn, Germany

[10] Goethe Univ Frankfurt, Inst Clin Neuroanat, Frankfurt, Germany

[11] AUSL n 2, Dept Neurosci, Caltanissetta, Italy

[12] Aristotle Univ Thessaloniki, Dept Neurol 3, GR-54006 Thessaloniki, Greece

[13] Univ Athens, Sch Med, Aeginition Hosp, Dept Neurol, GR-11527 Athens, Greece

[14] Netherlands Brain Bank, Amsterdam, Netherlands

来源：

NEURODEGENERATIVE DISEASES | 2005年 / 2卷 / 05期

关键词：

beta-Amyloid; Cholesterol; 25-hydroxylase; Dementia; Genetic association; Lathosterol; Susceptibility gene; Tau;

D O I：

10.1159/000090362

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25H chi 2, CH25H chi 3 and CH25H chi 4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25H chi 4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25H chi 4 and CH25H chi 3 haplotypes, whereas no A beta deposits were present in CH25H chi 2 carriers. Together, these results are compatible with a role of CH25H chi 4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition. Copyright (C) 2005 S. Karger AG, Basel

引用

页码：233 / 241

页数：9

共 34 条

[1] β-amyloid (Aβ) protein in cerebrospinal fluid as a biomarker for Alzheimer's disease [J].

Andreasen, N ;

Blennow, K .

PEPTIDES, 2002, 23 (07) :1205-1214

[2] Evidence for genetic linkage of Alzheimer's disease to chromosome 10q [J].

Bertram, L ;

Blacker, D ;

Mullin, K ;

Keeney, D ;

Jones, J ;

Basu, S ;

Yhu, S ;

McInnis, MG ;

Go, RCP ;

Vekrellis, K ;

Selkoe, DJ ;

Saunders, AJ ;

Tanzi, RE .

SCIENCE, 2000, 290 (5500) :2302-+

[3] NEUROPATHOLOGICAL STAGING OF ALZHEIMER-RELATED CHANGES [J].

BRAAK, H ;

BRAAK, E .

ACTA NEUROPATHOLOGICA, 1991, 82 (04) :239-259

[4] DETERMINATION OF CHOLESTEROL OXIDATION-PRODUCTS IN HUMAN PLASMA BY ISOTOPE-DILUTION MASS-SPECTROMETRY [J].

DZELETOVIC, S ;

BREUER, O ;

LUND, E ;

DICZFALUSY, U .

ANALYTICAL BIOCHEMISTRY, 1995, 225 (01) :73-80

[5] Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees [J].

Ertekin-Taner, N ;

Graff-Radford, N ;

Younkin, LH ;

Eckman, C ;

Baker, M ;

Adamson, J ;

Ronald, J ;

Blangero, J ;

Hutton, M ;

Younkin, SG .

SCIENCE, 2000, 290 (5500) :2303-+

[6]

GomezIsla T, 1996, J NEUROSCI, V16, P4491

[7]

Greeve I, 2000, J NEUROSCI, V20, P7345

[8] The family based association test method: strategies for studying general genotype-phenotype associations (Reprinted from European Journal of Human Genetics, Vol 9 pgs 301-306, 2001) [J].

Horvath, Steve ;

Xu, Xin ;

Laird, Nan M. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2017, 25 :S59-S62

[9] Functions of the upstream and proximal steroidogenic factor 1 (SF-1)-binding sites in the CYP11A1 promoter in basal transcription and hormonal response [J].

Hu, MC ;

Hsu, NC ;

Pai, CI ;

Wang, CKL ;

Chung, BC .

MOLECULAR ENDOCRINOLOGY, 2001, 15 (05) :812-818

[10] A NEW CLINICAL-SCALE FOR THE STAGING OF DEMENTIA [J].

HUGHES, CP ;

BERG, L ;

DANZIGER, WL ;

COBEN, LA ;

MARTIN, RL .

BRITISH JOURNAL OF PSYCHIATRY, 1982, 140 (JUN) :566-572

← 1 2 3 4 →