Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents.
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.
Hong
Hyun-Seok
HS
M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA,
Maezawa
Izumi
I
Budamagunta
Madhu
M
Rana
Sandeep
S
Shi
Aibin
A
Vassar
Robert
R
Liu
Ruiwu
R
Lam
Kit S
KS
Cheng
R Holland
RH
Hua
Duy H
DH
Voss
John C
JC
Jin
Lee-Way
LW
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D000682:Amyloid / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004123:Dimethylamines / Q000737:chemistry / Q000627:therapeutic use; D005449:Fluorenes / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011487:Protein Conformation
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D004123:Dimethylamines; D005449:Fluorenes; C554365:K01 162; C554366:K01 186