Can Early Targeting of Amyloid-beta 42 Channels Stop Alzheimer's Disease Before it Starts?

Abstract

Methods are currently being developed to diagnose early onset of Alzheimer's Disease (AD) before symptoms appear. The next logical step is to develop treatments to prevent farther progression of the disease; i.e., to nip AD in the bud before permeant damage occurs. Here we suggest targeting amyloid beta 42 (A?42) oligomers and transmembrane channels to achieve that goal. Although A?42 channels have not been well publicized, more than thirty years of research leaves little doubt that they exist and affect both synaptic and mitochondria membranes. Experimental evidence of these claims is review here along with highly constrained concentric ?-barrel molecular models of A?42 assemblies and their interactions with GM1 gangliosides in both aqueous and membrane environments. These models are consistent with well-developed transmembrane channel modeling criteria, are energetically sound, and are exceptionally stable throughout molecular dynamics simulations. Data used in developing these models include electron micrographs, single channel conductance measurements in both synthetic lipid bilayers and neurons, CD measurements of secondary structure in aqueous and membrane environments, NMR studies of A?42 assemblies in detergents, measurements of A?42 toxicity, and biochemical determination of which residues of A?42/GM1 assemblies are accessible to proteolytic cleavage.