Nobiletin Ameliorates Alzheimer’s Disease Pathology by Reducing Oxidative Stress and Neuroinflammation Through the AMPK/SIRT1/PGC-1α and PI3K/Akt–CREB–BDNF Pathways in 5XFAD Mice

Background/Objectives: Alzheimer’s disease (AD) involves amyloid-β (Aβ) deposition, oxidative stress, and neuroinflammation, leading to cognitive decline. Nobiletin, a citrus-derived polymethoxylated flavonoid, exerts antioxidant and anti-inflammatory effects. This study explored its neuroprotective mechanisms in the 5XFAD mouse model. Methods: Male 5XFAD and C57BL/6J mice received oral nobiletin (20 or 40 mg/kg/d) for 4 weeks. Cognitive function was assessed by the Y-maze test. Amyloid-β burden was quantified by Congo red staining and ELISA. Serum cytokine levels and antioxidant enzyme activities were measured by ELISA. Western blotting and RT-PCR were used to assess proteins and genes related to amyloidogenesis, inflammation (TLR4/MyD88/NF-κB), mitochondrial biogenesis (AMPK/SIRT1/PGC-1α), and synaptic plasticity (PI3K/Akt–CREB–BDNF). Results: Nobiletin improved working memory, reduced amyloid-β40/42 deposition, and downregulated APP, BACE1, and PS1 expression, while enhancing ADAM10 expression. It lowered serum IL-6, IL-1β, and TNF-α, increased SOD, CAT, and GPx activities, and suppressed TLR4/MyD88/NF-κB signaling. Furthermore, it activated AMPK/SIRT1/PGC-1α and NRF2 pathways, enhancing antioxidant defenses, and promoted PI3K/Akt–CREB–BDNF signaling, increasing PSD95 and synaptophysin. Conclusions: Nobiletin exerts strong neuroprotective and antioxidant effects by targeting multiple signaling cascades, mitigating amyloid pathology and neuroinflammation, and improving synaptic plasticity. It represents a promising therapeutic agent against AD.