Hesperetin And Nobiletin In Flavonoids Inhibit Amyloid β-protein Fibrilogenesis And Depolymerize Mature Fibrils

Alzheimer’s disease(AD)is one of the most common protein conformation diseases characterized by progressive cognitive decline and behavioral impairment.According to the amyloid cascade hypothesis,the misfolding,aggregation and deposition of amyloid β-protein(Aβ)in the brain is one of the main causes of AD.As the aging of the global population becomes increasingly serious,it is very important to develop effective inhibitors against Aβfibrosis for the prevention and treatment of AD.Hesperetin and nobiletin in dietary flavonoids are a class of natural flavonoids,widely existing in fruits,flowers,food and other plant sources,with anti-inflammatory,antioxidant and reduce the risk of AD in humans.However,their inhibition of Aβ fibrilogenesis and depolymerization on mature fibrils is not clear.We were first to systematically study that hesperetin and nobiletin in flavonoids inhibitβ-amyloid fibrilogenesis and depolymerize mature fibrils by biophysical,biochemical,cell biological and nematodes experiments.ThT fluorescence and AFM experiments confirmed that hesperetin inhibited Aβ fibrilogenesis in a dose-dependent manner.90μM hesperetin effectively blocked the structural transformation of Aβ40 from random coil to β-sheet,and promoted the depolymerized fibrils to form amorphous aggregates with less toxicity.The results of staining of transgenic C.elegans showed that hesperetin could reduce the Aβdeposition in CL4176 and reduce the effect of Aβ aggregation on the lifespan of C.elegans,extending the lifespan from 10 days to 12 days.Nobiletin is similar to hesperetin in structure,but it has multiple methoxyl groups.It is a flavonoid with strong biological activity.Nobiletin can inhibit Aβ aggregation,depolymerize mature Aβ fibrils,and reduce the cytotoxicity induced by Aβ aggregation in a concentration-dependent manner in vitro.Nobiletin itself has some nutritional effects on PC 12 cells.The results of ThT and AFM showed that nobiletin inhibits Aβ fibrilogenesis,which is consistent with hesperetin.The results of nematode experiment showed that nobiletin could also inhibit Aβ deposition in vivo and prolong the survival time of CL4176.These results not only revealed the inhibitory effect of hesperetin and nobiletin on Aβaggregation,but also revealed the possible inhibitory mechanism,which laid a solid foundation for the development of flavonoids against Aβ aggregation in the future.