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

NEUROBIOLOGY OF AGING

卷:31

Article

Hong, Hyun-Seok^1,2  Maezawa, Izumi^1,2  Budamagunta, Madhu³  Rana, Sandeep⁴  Shi, Aibin⁴  Vassar, Robert⁵  Liu, Ruiwu⁶  Lam, Kit S.⁶  Cheng, R. Holland⁷  Hua, Duy H.⁴  Voss, John C.³  Jin, Lee-Way^1,2 

[1] Univ Calif Davis, Med Ctr, Inst Pathol & Lab Med, MIND, Sacramento, CA 95817 USA

[2] Univ Calif Davis, Med Ctr, Dept Pathol & Lab Med, MIND, Sacramento, CA 95817 USA

[3] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA

[4] Kansas State Univ, Dept Chem, Manhattan, KS 66506 USA

[5] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA

[6] Univ Calif Davis, Med Ctr, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA

[7] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA

关键词: Amyloid-beta;    Alzheimer's disease;    Oligomer;    Small molecules;    Amyloid ligand;    Electron paramagnetic resonance spectroscopy;    Spin-label;    Synapse;   

DOI  :  10.1016/j.neurobiolaging.2008.09.019

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is characterized by depositions of beta-amyloid (A beta) 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 A beta oligomers (A beta O) with high affinities, they may also be valuable candidates for anti-A beta therapies. Here we identified two fluorene compounds from libraries of amyloid ligands, initially based on their ability to block cell death secondary to intracellular A beta O. We found that the lead fluorenes were able to reduce the amyloid burden including the levels of A beta O 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 A beta O as shown by electron paramagnetic resonance spectroscopy studies, and block the harmful A beta O-synapse interaction. These fluorenes and future derivatives, therefore, have a potential use in AD therapy and research. (C) 2008 Elsevier Inc. All rights reserved.

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