title: Small molecule NPT-440-1 inhibits ionic flux through Aβ1-42pores: Implications for Alzheimer's disease therapeutics.
abstract: Increased levels of soluble amyloid-beta (Aβ) oligomers are suspected to underlie Alzheimer's disease (AD) pathophysiology. These oligomers have been shown to form multi-subunit Aβ pores in bilayers and induce uncontrolled, neurotoxic, ion flux, particularly calcium ions, across cellular membranes that might underlie cognitive impairment in AD. Small molecule interventions that modulate pore activity could effectively prevent or ameliorate their toxic activity. Here we examined the efficacy of a small molecule, NPT-440-1, on modulating amyloid pore permeability. Co-incubation of B103 rat neuronal cells with NPT-440-1 and Aβ1-42prevented calcium influx. In purified lipid bilayers, we show that a 10-15min preincubation, prior to membrane introduction, was required to prevent conductance. Thioflavin-T and circular dichroism both suggested a reduction in Aβ1-42β-sheet content during this incubation period. Combined with previous studies on site-specific amino acid substitutions, these results suggest that pharmacological modulation of Aβ1-42could prevent amyloid pore-mediated AD pathogenesis.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Gillman
authors.affiliation: Department of Mechanical and Aerospace Engineering University of California, San Diego, La Jolla, CA, United States.
authors.forename: Joon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States; Department of Mechanical and Aerospace Engineering University of California, San Diego, La Jolla, CA, United States.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Capone
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States.
authors.forename: Tania
authors.initials: T
authors.lastname: Gonzalez
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States; Neuropore Therapies, Inc., San Diego, CA, United States.
authors.forename: Wolf
authors.initials: W
authors.lastname: Wrasidlo
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States. Electronic address: emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States; Materials Science and Engineering Program, University of California, San Diego, La Jolla, CA, United States; Department of Mechanical and Aerospace Engineering University of California, San Diego, La Jolla, CA, United States. Electronic address: rlal@eng.ucsd.edu.
authors.forename: Ratnesh
authors.initials: R
authors.lastname: Lal
mesh_terms: D000544:Alzheimer Disease / Q000628:therapy*; D000682:Amyloid; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D008051:Lipid Bilayers; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid beta peptide; Amyloid pore; Atomic force microscopy; Bilayer electrophysiology; Calcium; Small molecule