N-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 N-salicyloyl tryptamine derivatives can regulate mitochondrial function and effectively treat NDDs. Among them, compound N2 showed the best efficacy. This study first applied compound N2 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 N2 improved mitochondrial dysfunction and neuro-inflammation in PC12 or BV2 cells. N2 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 N2 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 N2 is a highly valuable anti-AD mitochondrial function regulator, providing a new strategy for the efficient treatment of AD.