Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo.
Small beta-amyloid (Abeta) 1-42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer's disease (AD). Methods to reduce the level of Abeta, prevent Abeta aggregation, and eliminate existing Abeta aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Abeta oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Abeta42 oligomer. Circular dichroism spectroscopy reveals monomeric Abeta42 peptide remains as a random coil/alpha-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Abeta42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Abeta42 oligomers and protofibrils. CP2 also blocks Abeta fibrillations using a protein quantification method. Treatment of 5x familial Alzheimer's disease mice, a robust Abeta42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Abeta species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Abeta aggregation and disaggregating existing Abeta oligomers and protofibrils.
Hong
Hyun-Seok
HS
M.I.N.D. Institute and Department of Pathology, UC Davis Health System, Sacramento, California 95817, USA.
Rana
Sandeep
S
Barrigan
Lydia
L
Shi
Aibin
A
Zhang
Yi
Y
Zhou
Feimeng
F
Jin
Lee-Way
LW
Hua
Duy H
DH
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D009454:Neurofibrils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000502:physiology; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; C512450:CP2 compound; D046911:Macromolecular Substances; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011108:Polymers; D011753:Pyrones; C075222:amyloid beta-protein (1-42)