Nobiletin Ameliorates Aβ₁–₄₂‐Induced Cognitive Disorder and Mitochondrial Dysfunction via Targeting the Key Circadian Regulator Bmal1

Alzheimer‘s disease is a neurodegenerative disease ​​characterized by​​ cognitive impairment and memory loss. The excessive accumulation of amyloid beta (Aβ) in brain is one of the pathogenesis of Alzheimer's disease. Nobiletin (NOB) is a kind of polymethoxy flavone that exists in some citrus fruits, which has a variety of health‐promoting functions, including anti‐inflammatory, antitumor, and anti‐obesity. However, the protective effects of NOB on Aβ 1–42 ‐induced oxidative stress and circadian dysfunction are not clear at the current stage. The current study showed that NOB treatment protected Aβ 1–42 ‐induced cognitive dysfunction, synaptic plasticity damage, and blunted circadian‐related protein. Furthermore, NOB treatment prevented Aβ 1–42 ‐induced cell apoptosis and mitochondrial damage in SH‐SY5Y cells. Moreover, Aβ 1–42 ‐induced circadian genes oscillations disorder and blunted Bmal1 and Clock protein expressions, which were prevented by NOB pretreatment. In addition, the present research revealed that the beneficial effects of NOB on mitochondrial function in Aβ 1–42 ‐treated cells were Bmal1‐dependent. In conclusion, our study revealed that NOB could be a potential compound in intervening AD via balancing circadian clock. In conclusion, our findings not only provide novel therapeutic insights for Alzheimer's disease but also contribute to Sustainable Development Goal 3 (Good Health and Well‐being) by addressing age‐related neurodegenerative disorders through natural compound intervention.