Su_2020_Neurochem.Int__104794

Cu(2+) plays a key role in the pathogenesis of Alzheimer's disease (AD). The dysregulation of Cu(2+) can cause neuronal damage and aggravate development of AD. Moreover, a series of 4-substituted sampangine derivatives have been investigated as inhibitors of acetylcholinesterase and beta-amyloid (Abeta) aggregation for the treatment of AD in our previous studies. In the present study, we reported that one of these derivatives SD-1 was able to modulate Cu(2+)-mediated multiple pathological elements in AD. The high selectivity of SD-1 for Cu(2+) over other biologically relevant metal ions was demonstrated by ITC. Western blotting analysis, light-scattering study, DCF-DA assay and paralysis experiment indicated that SD-1 suppressed the formation of Cu(2+)-Abeta species, alleviated the Cu(2+)-Abeta species induced neurotoxicity and inhibited the production of ROS catalyzed by Cu(2+)-Abeta species in SH-SY5Y cells over-expressing the Swedish mutant form of human APP (APPsw SH-SY5Y) and Abeta42 transgenic C elegans (CL2020). Furthermore, SD-1 inhibited the expressions of NO, iNOS, TNF-alpha, IL-1beta and IL-6 induced by Cu(2+) in BV2 microglial cells. Collectively, these findings provided valuable insights into the design and development of potent metal-chelating agents for AD treatment.