<i>N-</i> Salicyloyl Tryptamine Derivatives Improve Mitochondrial Function To Treat Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative disease (NDD) characterized by complex pathogenesis and remains incurable to date. Emerging evidence has demonstrated that mitochondrial dysfunction not only serves as a central component in AD initiation but also precedes other pathological processes, thereby playing a pivotal role in both the pathogenesis and progression of AD. Previous studies have confirmed that <i>N-</i>salicyloyl tryptamine derivatives can regulate mitochondrial function and effectively treat NDDs. Among them, compound <b>N2</b> showed the best efficacy. This study first applied compound <b>N2</b> to the treatment of AD and confirmed that it exerts anti-AD effects by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and enhancing the activity of mitochondrial complex I (MCI). The results showed that <b>N2</b> improved mitochondrial dysfunction and neuro-inflammation in PC12 or BV2 cells. <b>N2</b> was also shown to alleviate anxiety, cognitive impairment, neuronal damage, and amyloid-β (Aβ) pathological deposition in scopolamine-induced male Kunming mice. Mechanistic studies indicate that <b>N2</b> can reverse mitochondrial damage induced by rotenone (MCI inhibitor), as evidenced by reduced ROS levels and increased ATP levels; it also upregulates Nrf2 protein expression. These findings collectively indicate that <b>N2</b> is a highly valuable anti-AD mitochondrial function regulator, providing a new strategy for the efficient treatment of AD.