Candidate anti-Aβ fluorene compounds selected from analogs of amyloid imaging agents

Hyun Seok Hong, Izumi Maezawa, Madhu Budamagunta, Sandeep Rana, Aibin Shi, Robert Vassar, Ruiwu Liu, Kit Lam, R. Holland Cheng, Duy H. Hua, John C Voss, Lee-Way Jin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Alzheimer's disease (AD) is characterized by depositions of β-amyloid (Aβ) aggregates as amyloid in the brain. To facilitate diagnosis of AD by radioligand imaging, several highly specific small-molecule amyloid ligands have been developed. Because amyloid ligands display excellent pharmacokinetics properties and brain bioavailability, and because we have previously shown that some amyloid ligands bind the highly neurotoxic Aβ oligomers (AβO) with high affinities, they may also be valuable candidates for anti-Aβ therapies. Here we identified two fluorene compounds from libraries of amyloid ligands, initially based on their ability to block cell death secondary to intracellular AβO. We found that the lead fluorenes were able to reduce the amyloid burden including the levels of AβO in cultured neurons and in 5xFAD mice. To explain these in vitro and in vivo effects, we found that the lead fluorenes bind and destabilize AβO as shown by electron paramagnetic resonance spectroscopy studies, and block the harmful AβO-synapse interaction. These fluorenes and future derivatives, therefore, have a potential use in AD therapy and research.

Original languageEnglish (US)
Pages (from-to)1690-1699
Number of pages10
JournalNeurobiology of Aging
Volume31
Issue number10
DOIs
StatePublished - Oct 2010

Keywords

  • Alzheimer's disease
  • Amyloid ligand
  • Amyloid-β
  • Electron paramagnetic resonance spectroscopy
  • Oligomer
  • Small molecules
  • Spin-label
  • Synapse

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

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