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

Jacob R. Hascalovici, Jacob Vaya, Soliman Khatib, Christina A. Holcroft, Hillel Zukor, Wei Song, Zoe Arvanitakis, David A. Bennett, Hyman M. Schipper

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1241-1253
Number of pages13
JournalJournal of Neurochemistry
Volume110
Issue number4
DOIs
StatePublished - Aug 2009

Keywords

  • Alzheimer's disease
  • Cholesterol
  • Cholesterol precursors
  • Heme oxygenase-1
  • Lipids
  • Multivariable analysis
  • Oxysterols
  • Religious Orders Study

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Hascalovici, J. R., Vaya, J., Khatib, S., Holcroft, C. A., Zukor, H., Song, W., Arvanitakis, Z., Bennett, D. A., & Schipper, H. M. (2009). Brain sterol dysregulation in sporadic AD and MCI: Relationship to heme oxygenase-1. Journal of Neurochemistry, 110(4), 1241-1253. https://doi.org/10.1111/j.1471-4159.2009.06213.x