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

35 Citations (Scopus)

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 1 2009
Externally publishedYes

Fingerprint

Heme Oxygenase-1
Sterols
Brain
Alzheimer Disease
Cholesterol
Homeostasis
Aging of materials
Tissue
Cognitive Dysfunction
Proteins
Frontal Lobe
Metabolism
Astrocytes
Gas chromatography
Liver
Gas Chromatography-Mass Spectrometry
Mass spectrometry
Oxysterols
Up-Regulation
Enzyme-Linked Immunosorbent Assay

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

Cite this

Brain sterol dysregulation in sporadic AD and MCI : Relationship to heme oxygenase-1. / Hascalovici, Jacob R.; Vaya, Jacob; Khatib, Soliman; Holcroft, Christina A.; Zukor, Hillel; Song, Wei; Arvanitakis, Zoe; Bennett, David A.; Schipper, Hyman M.

In: Journal of Neurochemistry, Vol. 110, No. 4, 01.08.2009, p. 1241-1253.

Research output: Contribution to journalArticle

Hascalovici, JR, Vaya, J, Khatib, S, Holcroft, CA, Zukor, H, Song, W, Arvanitakis, Z, Bennett, DA & Schipper, HM 2009, 'Brain sterol dysregulation in sporadic AD and MCI: Relationship to heme oxygenase-1', Journal of Neurochemistry, vol. 110, no. 4, pp. 1241-1253. https://doi.org/10.1111/j.1471-4159.2009.06213.x
Hascalovici, Jacob R. ; Vaya, Jacob ; Khatib, Soliman ; Holcroft, Christina A. ; Zukor, Hillel ; Song, Wei ; Arvanitakis, Zoe ; Bennett, David A. ; Schipper, Hyman M. / Brain sterol dysregulation in sporadic AD and MCI : Relationship to heme oxygenase-1. In: Journal of Neurochemistry. 2009 ; Vol. 110, No. 4. pp. 1241-1253.
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