Hydroxycinnamic Acid from Corncob and Its Structural Analogues Inhibit A beta 40 Fibrillation and Attenuate A beta 40-Induced Cytotoxicity

摘要

The aggregation of amyloid-beta protein (A beta) is deemed a vital pathological feature of Alzheimer's disease (AD). Hence, inhibiting A beta aggregation is noticed as a major tactic for the prevention and therapy of AD. Hydroxycinnamic acid, as a natural phenolic compound, is widely present in plant foods and has several biological activities including anti-inflammation, antioxidation, and neuroprotective effects. Here, it was found that hydroxycinnamic acid and its structural analogues (3-hydroxycinnamic acid, 2-hydroxycinnamic acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 2,4-dihydroxycinnamic acid, and 3,4,5-trihydroxycinnamic acid) could inhibit A beta 40 fibrillogenesis and reduce A beta 40-induced cytotoxicity in a dose-dependent manner. Among these small molecules investigated, 3,4,5-trihydroxycinnamic acid is considered to be the most effective inhibitor, which reduces the ThT fluorescence intensity to 30.79% and increases cell viability from 49.47 to 84.78% at 200 mu M. Also, the results with Caenorhabditis elegans verified that these small molecules can ameliorate AD-like symptoms of worm paralysis. Moreover, molecular docking studies showed that these small molecules interact with the A beta 40 mainly via hydrogen bonding. These results suggest that hydroxycinnamic acid and its structural analogues could inhibit A beta 40 fibrillogenesis and the inhibition activity is enhanced with the increase of phenolic hydroxyl groups of inhibitors. These small molecules have huge potential to be developed into novel aggregation inhibitors in neurodegenerative disorders.