Preventive action of nobiletin, a constituent of Aurantii Nobilis Pericarpium with anti-dementia activity, against amyloid-β 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 β-amyloid (Aβ) 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 Aβ 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 Aβ-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 Aβ 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 Aβ in cultured hippocampal neurons. Our in vitro studies evidently showed that a sublethal concentration of Aβ actually inhibited glutamate-induced increases in both PKA substrates phosphorylation and GluR1 membrane trafficking in cultured hippocampal neurons, whereas nobiletin reversed the Aβ-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.