Flavonoids and Fibrate modulate APOE4‐induced processing of Amyloid precursor protein in rat neuronal cells

Abstract

Several studies reported a role of Apolipoprotein E4 (ApoE4) in processing Amyloid precursor protein (APP) to Amyloid β (Aβ) peptide, thus playing a major role in Alzheimer's disease. This study, investigated the effect of flavonoids and fenofibrate, a hypolipidemic agent, on ApoE4‐induced APP processing in B103 cells stably transfected with human wild‐type APP695. Cells were pretreated with varying doses of flavonoids and fenofibrate for 1 hour, prior to ApoE4 exposure for 24 hours. Results showed that pretreatment with fisetin and diosmetin significantly reduced, whereas naringenin and fenofibrate had no effect on APOE4‐increased expression of APP. In addition, the expression of carboxy terminal fragments‐α and ‐β generated by the α‐ or β‐secretase cleavage of APP increased significantly in cells pretreated with fisetin as compared to disometin, naringenin, and fenofibrate. Conditioned medium collected from treated B103‐APP cells were used to treat Rat pheochoromocytoma (PC12) cells and cell viability assay showed more pronounced effect of flavonoids on reversing ApoE4 induced cell death as compared to fenofibrate. β‐secretase activity showed that flavonoids may not have a direct effect on the enzyme but may increase APP processing and prevent cell death, most likely through a decrease in Aβ production as reported by the conditioned media experiment. This work was supported by Long Island University, NY.