Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo |
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Authors: | Hyun-Seok Hong Sandeep Rana† Lydia Barrigan† Aibin Shi† Yi Zhang‡ Feimeng Zhou‡ Lee-Way Jin Duy H Hua† |
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Institution: | M.I.N.D. Institute and Department of Pathology, UC Davis Health System, Sacramento, California, USA; Department of Chemistry, Kansas State University, Manhattan, Kansas, USA; Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California, USA |
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Abstract: | 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 5× 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. |
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Keywords: | 5× familial Alzheimer's disease mice anti-β-amyloid effect atomic force microscopy disaggregation of Aβ oligomers and protofibrils inhibition of Aβ fibrillation tricyclic pyrone CP2 |
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