Small molecule NPT-440-1 inhibits ionic flux through Aβ1 -42 pores: Implications for Alzheimer's disease therapeutics

Increased levels of soluble amyloid-beta (Aβ) oligomers are suspected to underlie Alzheimer's disease (AD) pathophysiology through the formation of uncontrolled multi-subunit Aβ pores in cellular membranes. In this study, the efficacy of small molecule NPT-440-1 modulation of Aβ1 -42 pore permeability was examined. We show that co-incubation of B103 rat neuronal cells with NPT-440-1 and Aβ1 -42 prevented calcium influx. In purified lipid bilayers, preincubation prior to membrane introduction was required to prevent conductance despite the presence of pore structures. The results point to compound-induced structural modulation leading to collapsed pores and suggest that pharmacological modulation of Aβ1 -42 could prevent AD pathogenesis.89