Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1 |
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Authors: | Jacob R. Hascalovici&dagger ,Jacob Vaya&Dagger ,Soliman Khatib&Dagger ,Christina A. Holcroft§ ,Hillel Zukor&dagger ,Wei Song,Zoe Arvanitakis¶ ,David A. Bennett¶ , Hyman M. Schipper&dagger |
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Affiliation: | Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Dept. of Neurology and Neurosurgery, McGill University;SMBD Jewish General Hospital, Montreal, Quebec, Canada; Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center and Tel Hai College, Kiryat-Shmona, Israel; Centre for Clinical Epidemiology and Community Studies, SMBD Jewish General Hospital, Montreal, Quebec, Canada; Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA |
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Abstract: | 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. |
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Keywords: | Alzheimer's disease cholesterol cholesterol precursors heme oxygenase-1 lipids multivariable analysis oxysterols Religious Orders Study |
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