*Article* **Discovery of Nobiletin from Citrus Peel as a Potent Inhibitor of** β**-Amyloid Peptide Toxicity**

**Kumju Youn 1,**†**, Seonah Lee 1,2,**† **and Mira Jun 1,2,\***


Received: 7 October 2019; Accepted: 29 October 2019; Published: 4 November 2019

**Abstract:** Increasing evidence has demonstrated that amyloid-β peptide (Aβ), the hallmark of Alzheimer's disease (AD), evokes oxidative and inflammatory cascades, which ultimately lead to the death of neurons. The purpose of the present study is to demonstrate the effect of nobiletin, a representative compound of citrus peel, in preventive and therapeutic approaches against neuronal damage by exposure to Aβ25–35. Nobiletin significantly ameliorated Aβ25–35-mediated cell death by restoring abnormal changes in intracellular oxidative stress, cell cycle, nuclear morphology, and activity of apoptotic caspase. Regarding anti-inflammatory responses, nobiletin significantly suppressed interleukin-1β, tumor necrosis factor-<sup>α</sup>, nitric oxide (NO), and prostaglandin E2 production in response to Aβ stimulation. Moreover, nobiletin inhibited Aβ-stimulated inducible NO synthase and cyclooxygenase-2 expression, which was attributed to the blockade of nuclear factor-κB p65 and phosphorylation of its inhibitor, IκB-α. Interestingly, nobiletin decreased expression of c-Jun N-terminal kinase and p38 without affecting extracellular signal-regulated kinase 1/2 activation. Taken together, the novel data implicate nobiletin as a potential candidate for the prevention of AD through the inhibition of oxidative stress, apoptosis, and inflammation.

**Keywords:** Alzheimer's disease; amyloid-β peptide; oxidative stress; inflammation; nobiletin
