Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo

• Published in: Journal of neurochemistry Vol. 108; no. 4; pp. 1097 - 1108
• Main Authors: Hong, Hyun-Seok, Rana, Sandeep, Barrigan, Lydia, Shi, Aibin, Zhang, Yi, Zhou, Feimeng, Jin, Lee-Way, Hua, Duy H
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.02.2009; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: 5x familial Alzheimer's disease mice; 5× familial Alzheimer’s disease mice; Adult and adolescent clinical studies; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; anti-β-amyloid effect; Antidepressants; atomic force microscopy; Binding Sites - drug effects; Binding Sites - physiology; Binding, Competitive - drug effects; Binding, Competitive - physiology; Biochemistry; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; disaggregation of Aβ oligomers and protofibrils; Disease Models, Animal; Disease prevention; Down-Regulation - drug effects; Down-Regulation - physiology; inhibition of Aβ fibrillation; Macromolecular Substances - metabolism; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Transgenic; Molecular Structure; Neurofibrils - drug effects; Neurofibrils - metabolism; Neurofibrils - pathology; Neurology; Neurons; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Organic mental disorders. Neuropsychology; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Plaque, Amyloid - drug effects; Plaque, Amyloid - metabolism; Polymers - metabolism; Protein Structure, Secondary - drug effects; Protein Structure, Secondary - physiology; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Pyrones - pharmacology; Pyrones - therapeutic use; Treatment Outcome; tricyclic pyrone CP2; Atomic force microscopy; Animal model; Peptides; Alzheimer disease; Toxicity; disaggregation of Aβ oligomers and protofibrils; Aggregation; Familial disease; Fibrillation; Degenerative disease; Curcumin; anti-β- amyloid effect; Nervous system diseases; Rodentia; In vitro; Protein; Cerebral disorder; Vertebrata; Mammalia; Neuron; Treatment; Mouse; Cell death; Central nervous system disease; tricyclic pyrone CP2; 5x familial Alzheimer's disease mice; inhibition of Aβ fibrillation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05866.x

Small β-amyloid (Aβ) 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 Aβ, prevent Aβ aggregation, and eliminate existing Aβ aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Aβ oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Aβ42 oligomer. Circular dichroism spectroscopy reveals monomeric Aβ42 peptide remains as a random coil/α-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Aβ42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Aβ42 oligomers and protofibrils. CP2 also blocks Aβ fibrillations using a protein quantification method. Treatment of 5x familial Alzheimer's disease mice, a robust Aβ42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Aβ aggregation and disaggregating existing Aβ oligomers and protofibrils.