Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo

Hyun Seok Hong, Sandeep Rana, Lydia Barrigan, Aibin Shi, Yi Zhang, Feimeng Zhou, Lee-Way Jin, Duy H. Hua

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Small β-amyloid (Aβ) 1-42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer's disease (AD). Methods to reduce the level of Aβ, prevent Aβ aggregation, and eliminate existing Aβ aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Aβ oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Aβ42 oligomer. Circular dichroism spectroscopy reveals monomeric Aβ42 peptide remains as a random coil/α-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Aβ42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Aβ42 oligomers and protofibrils. CP2 also blocks Aβ fibrillations using a protein quantification method. Treatment of 5x familial Alzheimer's disease mice, a robust Aβ42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Aβ aggregation and disaggregating existing Aβ oligomers and protofibrils.

Original languageEnglish (US)
Pages (from-to)1097-1108
Number of pages12
JournalJournal of Neurochemistry
Volume108
Issue number4
DOIs
StatePublished - Feb 2009

Keywords

  • 5x familial Alzheimer's disease mice
  • Anti-β-amyloid effect
  • Atomic force microscopy
  • Disaggregation of Aβ oligomers and protofibrils
  • Inhibition of Aβ fibrillation
  • Tricyclic pyrone CP2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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