AMYLOID ION CHANNEL TOXICITY: DISRUPTION OF B-SHEET STRUCTURE PREVENTS TOXIC IONIC FLUX THROUGH AB PORES

Abstract

A common mechanism underlying Alzheimer's disease (AD) pathophysiology relies upon increased levels of soluble amyloid-beta (Aβ) oligomers. These oligomers induce uncontrolled ion flux across cellular membranes resulting in the dysregulation of ionic homeostasis, particularly calcium ions. High calcium concentration is known to cause neuronal degeneration and death that might underlie AD cognitive impairment. Previous 3D structural analysis, using atomic force microscopy (AFM), in our laboratory has shown that Aβ forms multi-subunit ion channels (Figure A, inset). These ion channel structures are complemented by the expected ionic permeability and single channel conductance of calcium and other cations in purified bilayer preparations. Amyloid ion channel structure-activity relationships are tightly interlinked; pharmacological and small molecule interventions that modulate channel structure could be then become an effective strategy to prevent their toxic activity. In this study, we examined pharmacologic intervention in reducing ionic flux through A β ion channels. Aβ(1-42) ion channels were reconstituted in planar lipid bilayers (PLB) and electrical conductance recordings were analyzed both in the presence as well as in the absence of a defined pharmacological agent. The pharmacological agent used in the study is a proprietary and experimental compound provided by Neuropore Therapies Inc. (La Jolla, CA). Short pre-incubation (∼10 min) of the compound with Aβ(1-42) effectively prevented ion channel conductance (Figure C). However, the compound added along with A β(1-42) showed no change in ionic conductance (Figure B) vs. the control with A β(1-42) alone (Figure A), even at much higher compound concentrations.