O1‐11‐04: Naturally occurring beta‐secretase inhibitors mitigate behavioral impairment, cerebral amyloidosis and neuroinflammation in transgenic mice

The secretases are essential for cleavage of amyloid precursor protein (APP), and give rise to either non-amyloidogenic (a-secretase) or amyloidogenic (β- followed by g-secretase) proteolytic products. One of the key Alzheimer disease (AD) treatment strategies currently being tested in the clinic is inhibition of β- or g-secretase activity using designer drugs. However, such approaches can have serious negative side-effects. Owing to their existence throughout evolution, natural compounds ('nutraceuticals') tend to have a favorable safety profile, and we previously showed that the green tea-derived compound epigallocatechin gallate promotes a-secretase activity and reduces cerebral amyloid pathology in transgenic mice. Based on these previous results, we further evaluated a class of plant-derived nutraceuticals with pleiotropic activities, known as flavonoids, as modulators of secretase activity. We therefore orally administered tannic acid and ferulic acid in a disease prevention paradigm to the PSAPP transgenic mouse model of cerebral amyloidosis, and assessed behavior and AD-like pathology. PSAPP and wild-type mice were given ad libitum access to chow containing either compound, beginning at 6 months of age and for a period of 6 months thereafter. We also carried out mechanistic investigations in vitro and in cell-free systems. Interestingly, either compound prevented or delayed 1) cognitive impairment, 2) cerebral amyloidosis (by histochemical and biochemical analyses) and 3) neuroinflammation (by gliosis immunohistochemistry and cytokine analyses). Furthermore, in vitro and cell-free assays revealed that either tannic or ferulic acid effectively inhibited β-secretase expression and activity. If results in these pre-clinical mouse models translate to human AD, our data suggest that dietary supplementation with tannic and/or ferulic acid may prevent or delay development of AD pathology by inhibiting expression and activity of β-secretase.