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

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.

Abbreviations: AD, Alzheimer's disease, Aβ, β-amyloid protein, AβO, Aβ oligomers, BBB, blood–brain barrier, CR, Congo red, SPR, surface plasmon resonance spectroscopy, EPR, electron paramagnetic resonance spectroscopy, AFM, atomic force microscopy, EM, electron microscopy, RIPA, radioimmune precipitation assay, HRP, horse radish peroxidase

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