Activity and architecture of pyroglutamate-modified amyloid-? (A?pE3-42) pores.

ABSTRACT: Among the family of A? peptides, pyroglutamate-modified A? (A?pE) peptides are particularly associated with cytotoxicity in Alzheimer's disease (AD). They represent the dominant fraction of A? oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of A?pE plaques precedes the formation of plaques of full-length A? (A?1-40/42). Most of these properties appear to be associated with the higher hydrophobicity of A?pE as well as an increased resistance to enzymatic degradation. However, the important question of whether A?pE peptides induce pore activity in lipid membranes and their potential toxicity compared with other A? pores is still open. Here we examine the activity of A?pE pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that A?pE pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the A? family. However, there are also some significant differences. The onset of A?pE3-42 pore activity is generally delayed compared with A?1-42 pores. However, once formed, A?pE3-42 pores produce increased ion permeability of the membrane, as indicated by a greater occurrence of higher conductance electrical events. Structurally, the lactam ring of A?pE peptides induces a change in the conformation of the N-terminal strands of the A?pE3-42 pores. While the N-termini of wild-type A?1-42 peptides normally reside in the bulk water region, the N-termini of A?pE3-42 peptides tend to reside in the hydrophobic lipid core. These studies provide a first step to an understanding of the enhanced toxicity attributed to A?pE peptides.

SUBMITTER: Gillman AL 

PROVIDER: S-EPMC4096221 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature