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22R-Hydroxycholesterol protects neuronal cells from beta-amyloid-induced cytotoxicity by binding to beta-amyloid peptide.

Abstract
22R-hydroxycholesterol, a steroid intermediate in the pathway of pregnenolone formation from cholesterol, was found at lower levels in Alzheimer's disease (AD) hippocampus and frontal cortex tissue specimens compared to age-matched controls. beta-Amyloid (Abeta) peptide has been shown to be neurotoxic and its presence in brain has been linked to AD pathology. 22R-hydroxycholesterol was found to protect, in a dose-dependent manner, against Abeta-induced rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma (NT2N) neuron cell death. Other steroids tested were either inactive or acted on rodent neurons only. The effect of 22R-hydroxycholesterol was found to be stereospecific because its enantiomer 22S-hydroxycholesterol failed to protect the neurons from Abeta-induced cell death. Moreover, the effect of 22R-hydroxycholesterol was specific for Abeta-induced cell death because it did not protect against glutamate-induced neurotoxicity. The neuroprotective effect of 22R-hydroxycholesterol was seen when using Abeta1-42 but not the Abeta25-35 peptide. To investigate the mechanism of action of 22R-hydroxycholesterol we examined the direct binding of this steroid to Abeta using a novel cholesterol-protein binding blot assay. Using this method the direct specific binding, under native conditions, of 22R-hydroxycholesterol to Abeta1-42 and Abeta17-40, but not Abeta25-35, was observed. These data suggest that 22R-hydroxycholesterol binds to Abeta and the formed 22R-hydroxycholesterol/Abeta complex is not toxic to rodent and human neurons. We propose that 22R-hydroxycholesterol offers a new means of neuroprotection against Abeta toxicity by inactivating the peptide.
AuthorsZhi-Xing Yao, Rachel C Brown, Gary Teper, Janet Greeson, Vassilios Papadopoulos
JournalJournal of neurochemistry (J Neurochem) Vol. 83 Issue 5 Pg. 1110-9 (Dec 2002) ISSN: 0022-3042 [Print] England
PMID12437582 (Publication Type: Journal Article)
Chemical References
  • Amyloid beta-Peptides
  • Hydroxycholesterols
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • amyloid beta-protein (25-35)
  • 22-hydroxycholesterol
  • Glutamic Acid
Topics
  • Aged
  • Amyloid beta-Peptides (antagonists & inhibitors, chemistry, metabolism, toxicity)
  • Animals
  • Binding, Competitive (drug effects)
  • Cell Death
  • Cell Line
  • Computer Simulation
  • Female
  • Frontal Lobe (chemistry)
  • Glutamic Acid (toxicity)
  • Hippocampus (chemistry)
  • Humans
  • Hydroxycholesterols (chemistry, metabolism, pharmacology)
  • Male
  • Models, Molecular
  • Neurons (cytology, drug effects, metabolism)
  • Neuroprotective Agents (analysis, metabolism, pharmacology)
  • PC12 Cells
  • Peptide Fragments (antagonists & inhibitors, chemistry, metabolism, toxicity)
  • Protein Binding (physiology)
  • Rats
  • Stereoisomerism
  • Substrate Specificity

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