Hydroxycinnamic acid from Corncob and Its Structural Analogues Inhibit Aβ40 Fibrillation and Attenuate Aβ40-Induced Cytotoxicity

The aggregation of amyloid-β protein (Aβ) is deemed a vital pathological feature of Alzheimer's disease (AD). Hence, inhibiting Aβ 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 Aβ40 fibrillogenesis and reduce Aβ40-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 ThT fluorescence intensity to 30.79% and increases cell viability from 49.47% to 84.78% at 200 µM. And the results with C. elegans tested that these small molecules can ameliorate AD-like symptoms of worm paralysis. Moreover, molecular docking studies showed that these small molecules interact with the Aβ40 mainly via hydrogen-bonding. These results suggest that hydroxycinnamic acid and its structural analogues could inhibit Aβ40 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 a novel aggregation inhibitor in neurodegenerative disorders.