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Probing structural features of amyloid-beta Ion channels in membranes using A-beta mutants

  • Author(s): Kotler, Samuel Aaron
  • et al.
Abstract

A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-beta (A[beta]) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The resulting inability of neurons to regulate their intracellular concentration of ions, in particular calcium ions, has been associated with cell death and may thus contribute to cognitive impairment typical for AD. The mechanism of the ion flux is not fully understood since no experimentally based A[beta] channel structures at atomic resolution are currently available, and few polymorphisms have been predicted by computational models. Structural models and experimental evidence suggest that A[beta] channel is an assembly of loosely-associated mobile [beta]-sheet subunits. Using planar lipid bilayers, we present a study showing that amino acidic substitutions can be used to infer which residues are essential for channel structure and/or line the pore. We tested: A[beta]42-F19P, A[beta]42-F20C, A[beta]42-A42C, and A[beta]42-D1C. The substitution of F19P inhibited channel formation. All the cysteine mutants tested are capable of forming channels, but with different characteristics. This and other structural information on or in membrane are needed to aid the understanding of channel formation and structure. Additionally, this information should aid studies of drug design aiming to control unregulated A[beta] ion fluxes

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