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

Abstract

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 Aβ 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 Aβ immunoassays confirmed that nobiletin also significantly decreased the levels of Aβ 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.

Nobiletin Delays Aging and Enhances Stress Resistance of Caenorhabditis elegans

“…Previous studies have shown that NOB has strong antimicrobial, antioxidant, anti-proliferative, anti-inflammatory, and anti-dementia activities [26,[30][31][32][33][34][35]. Convincing evidence has shown that NOB promotes healthy aging in aged male mice with regular or high-fat diets, which works against metabolic disorders and aging-related energy imbalance, including restoring glucose homeostasis, promoting energy expenditure, cold tolerance and circadian activity, optimizing mitochondrial respiratory chain complexes (MRCs) activity and architecture in aged skeletal muscle, and regulating cholesterol and bile acid metabolism [27,36]. In this study, we further explored whether NOB has an effect on aging using the short-lived model organism, C. elegans.…”

Modeling Alzheimer’s disease with iPSC-derived brain cells

“…The development of iPSC technologies provides the attractive possibility of using differentiated human cells as platforms for drug and mutagenesis screening, reviewed by Elitt and colleagues [180]. Multiple small-scale compound screens using differentiated neuronal subtypes have already targeted disease-related pathways in AD [39,[181][182][183][184], Parkinson's Disease [185], Huntington's Disease [186], and frontotemporal dementia [187]. A recent effort screened over 1600 compounds for reductions of tau phosphorylation in FAD neurons, identifying numerous hits and ultimately moving forward our understanding of the biology underlying p-tau accumulation [188].…”

Human-Derived Brain Models: Windows into Neuropsychiatric Disorders and Drug Therapies

“…38,39 Nobiletin reduced intracellular and secreted Ab in hIPSC-derived neurons with an fAD-associated presenilin-1 mutation. 40 The observed protherapeutic effect is due to increased expression of the Ab-degrading enzyme, neprilysin. 40 Similarly, apigenin, the polyphenolic compound found in celery, parsley, and artichoke, exhibited neuroprotective effects in hIPSC-derived sAD and fAD neurons.…”

“…40 The observed protherapeutic effect is due to increased expression of the Ab-degrading enzyme, neprilysin. 40 Similarly, apigenin, the polyphenolic compound found in celery, parsley, and artichoke, exhibited neuroprotective effects in hIPSC-derived sAD and fAD neurons. 41 Apigenin's anti-inflammatory properties reduced nitric oxide production, increased neurite length, and rescued cell viability.…”