Preventive Action of Nobiletin, a Constituent of AURANTII NOBILIS PERICARPIUM with Anti-dementia Activity, against Amyloid-beta Peptide-induced Neurotoxicity Expression and Memory Impairment

Alzheimer's disease (AD) has become a major health burden to society. However, no fundamentally therapeutic drugs for AD have been developed. Increasing evidence suggests that the elevation of beta-amyloid (A beta) peptides in the brain is central to AD pathogenesis. Recently, in the course of our survey of substances having anti-dementia activity from natural resources, we have successfully found nobiletin, a polymethoxylated flavone contained in AURANTII NOBILIS PERICARPIUM which is a component of traditional Chinese medicines. In this review, we describe the beneficial effects of nobiletin on memory impairment and A beta pathology in a transgenic mouse model introduced human Swedish and London mutant amyloid precursor protein. We also note the possible molecular mechanism underlying the protective action against A beta-induced memory impairment provided by our studies using cultured hippocampal neurons. Namely, daily administration of nobiletin for four months rescued the memory impairment in fear conditioning, and decreased hippocampal A beta deposit in the transgenic mice as analyzed by immunohistochemistry. PKA-dependent signaling and membrane trafficking of AMPA receptor subunit, GluR1, which are known to be required for long-term potentiation (LTP), have been demonstrated to be inhibited by a sublethal concentration of A beta in cultured hippocampal neurons. Our in vitro studies evidently showed that a sublethal concentration of A beta actually inhibited glutamate-induced increases in both PKA substrates phosphorylation and GluR1 membrane trafficking in cultured hippocampal neurons, whereas nobiletin reversed the A beta-induced inhibition of such biochemical processes. The natural compound with these unique actions has thus potential to become a novel drug for fundamental treatment of AD.