Send to

Choose Destination
Biol Pharm Bull. 2018;41(4):451-457. doi: 10.1248/bpb.b17-00364.

Nobiletin Reduces Intracellular and Extracellular β-Amyloid in iPS Cell-Derived Alzheimer's Disease Model Neurons.

Author information

Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka.
Sankyo Co., Ltd.
Department of Medicinal Pharmacognosy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
Kansei Fukushi Research Institute, Tohoku Fukushi University.


Alzheimer's disease (AD) is the most common cause of dementia, with progressive memory impairment. Recently, neprilysin, a β-amyloid (Aβ)-degrading enzyme has become featured as a drug target for AD. Previously, we identified nobiletin from citrus peels as a natural compound possessing anti-dementia activity. In addition, we demonstrated that nobiletin improved memory in memory-impaired animals and, further, that Aβ levels were markedly decreased in the brains of these animals. We demonstrated in vitro that nobiletin up-regulates neprilysin expression and activity in human neuroblastoma cells. However, the action of nobiletin with regard to Aβ degradation under in vitro AD pathological conditions remains unclear. In this study, we examined whether nobiletin could enhance the degradation of intra- and extracellular Aβ using human induced pluripotent stem cell-derived AD model neurons, which generate an excess of Aβ1-42 due to the familial AD presenilin-1 mutation. The neurons were treated in the presence or absence of nobiletin. The results of real-time quantitative RT-PCR indicated that neprilysin mRNA levels were significantly up-regulated by nobiletin. Furthermore, immunostaining with an anti-Aβ antibody revealed that nobiletin substantially reduced the intraneuronal content of Aβ. Interestingly, the results of Aβ1-42 immunoassays confirmed that nobiletin also significantly decreased the levels of Aβ1-42 released into the cellular medium. These results suggest that nobiletin enhanced the reduction of intra- and that extracellular Aβ levels under AD pathologic conditions, and this is associated with the up-regulation of neprilysin expression. Collectively, nobiletin appears to be a promising novel prophylactic seed drug or functional food for AD.


gene expression; induced pluripotent stem (iPS) cell-derived Alzheimer’s disease model neuron; neprilysin; nobiletin; β-amyloid

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for J-STAGE, Japan Science and Technology Information Aggregator, Electronic
Loading ...
Support Center