Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1

被引:54
作者
Hascalovici, Jacob R. [1 ,2 ]
Vaya, Jacob [3 ,4 ]
Khatib, Soliman [3 ,4 ]
Holcroft, Christina A. [5 ]
Zukor, Hillel [1 ,2 ]
Song, Wei [1 ]
Arvanitakis, Zoe [6 ,7 ]
Bennett, David A. [6 ,7 ]
Schipper, Hyman M. [1 ,2 ]
机构
[1] SMBD Jewish Gen Hosp, Lady Davis Inst Med Res, Ctr Neurotranslat Res, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2T5, Canada
[3] Migal Gelilee Technol Ctr, Lab Nat Med Cpds, Kiryat Shmona, Israel
[4] Tel Hai Coll, Kiryat Shmona, Israel
[5] SMBD Jewish Gen Hosp, Ctr Clin Epidemiol & Community Studies, Montreal, PQ H3T 1E2, Canada
[6] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA
[7] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA
基金
加拿大健康研究院;
关键词
Alzheimer's disease; cholesterol; cholesterol precursors; heme oxygenase-1; lipids; multivariable analysis; oxysterols; Religious Orders Study; MILD COGNITIVE IMPAIRMENT; AMYLOID PRECURSOR PROTEIN; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; CHOLESTEROL-SYNTHESIS; RISK-FACTORS; OXYSTEROLS; EXPRESSION; HOMEOSTASIS; PROTECTOR;
D O I
10.1111/j.1471-4159.2009.06213.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The objective of this study was to ascertain the impact of aging and Alzheimer's disease (AD) on brain cholesterol (CH), CH precursors, and oxysterol homeostasis. Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from postmortem human frontal cortex derived from subjects with sporadic AD, mild cognitive impairment (MCI), and no cognitive impairment (n = 17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. ELISA was used to quantify human HO-1 protein expression from brain tissue and gas chromatography-mass spectrometry to quantify total CH, CH precursors, and relevant oxysterols. The relationships of sterol/oxysterol levels to HO-1 protein expression and clinical/demographic variables were determined by multivariable regression and non-parametric statistical analyses. Decreased CH, increased oxysterol and increased CH precursors concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not no cognitive impairment. Specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological impairment, and age. A model featuring compensated and de-compensated states of altered sterol homeostasis in MCI and AD is presented based on the current data set and our earlier in vitro work.
引用
收藏
页码:1241 / 1253
页数:13
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