A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes

Izumi Maezawa, Hyun Seok Hong, Hui Chuan Wu, Srinivas K. Battina, Sandeep Rana, Takeo Iwamoto, Gary A. Radke, Erik Pettersson, George M. Martin, Duy H. Hua, Lee-Way Jin

Research output: Contribution to journalArticle

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Abstract

The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites.

Original languageEnglish (US)
Pages (from-to)57-67
Number of pages11
JournalJournal of Neurochemistry
Volume98
Issue number1
DOIs
StatePublished - Jul 2006

Fingerprint

Pyrones
Cell death
Amyloid
Toxicity
Alzheimer Disease
Cell Death
Serum Amyloid A Protein
Neuroblastoma
Oligomers
Neurons
Oligomerization
Agglomeration
Therapeutics

Keywords

  • Alzheimer's disease
  • Amyloid
  • Intracellular
  • Oligomer
  • Small molecule
  • Toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes. / Maezawa, Izumi; Hong, Hyun Seok; Wu, Hui Chuan; Battina, Srinivas K.; Rana, Sandeep; Iwamoto, Takeo; Radke, Gary A.; Pettersson, Erik; Martin, George M.; Hua, Duy H.; Jin, Lee-Way.

In: Journal of Neurochemistry, Vol. 98, No. 1, 07.2006, p. 57-67.

Research output: Contribution to journalArticle

Maezawa, Izumi ; Hong, Hyun Seok ; Wu, Hui Chuan ; Battina, Srinivas K. ; Rana, Sandeep ; Iwamoto, Takeo ; Radke, Gary A. ; Pettersson, Erik ; Martin, George M. ; Hua, Duy H. ; Jin, Lee-Way. / A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes. In: Journal of Neurochemistry. 2006 ; Vol. 98, No. 1. pp. 57-67.
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