Spectroscopic investigation of the effect of polyphenolic compounds on the amyloid-β protein
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Aggregation of the amyloid-β (Aβ) protein is associated with the development of Alzheimer's disease. Aβ is a 39-43 residue cleavage product of the amyloid precursor protein (APP). Aβ aggregates to produce insoluble plaques in the brain, which are composed of cross β-sheet structured fibrils. Various polyphenolic compounds, both naturally occurring and synthetic, have been shown to interfere with Aβ aggregation. To evaluate the ability of specific polyphenols to prevent Aβ aggregation, this investigation utilized nordihydroguaiaretic acid, curcumin, rosmarinic acid, resveratrol, piceatannol, and diethylstilbestrol. These polyphenols differ in the number of ring substituents and the atom linker between the rings. The interaction of Aβ with the polyphenolic compounds was analyzed using circular dichroism (CD) and deep ultraviolet resonance Raman (dUVRR) spectroscopies. The polyphenols diethylstilbestrol, resveratrol, and piceatannol have increasing numbers of hydroxyl substituents on their rings, having two, three, and four respectively. It was found that with increasing number of hydroxyl ring substituents, the protein remained predominantly disordered and prevented formation of β-structure in the protein and aided in the destabilization of pre-formed Aβ fibrils. Decreasing the number of hydroxyl substituents increases the likelihood of β-sheet formation, prevented destabilization of pre-formed Aβ fibrils, and induced loss of stability of the protein. The polyphenols nordihydroguaiaretic acid, curcumin, and rosmarinic acid have increasing polarity respectively in the chain linker between the phenolic rings. Each of these polyphenols have four ring substituents and have four to six atoms in their chain linker. It was found that with increasing the polarity of the linker, the protein had a greater tendency to form a β-structure, however pre-formed Aβ fibrils were destabilized efficiently by all three polyphenols. Though a nonpolar chain linker pushed fibrillar protein toward a more disordered structure initially, the final state was similar regardless of added polyphenol.
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