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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: