Among the family of A beta peptides, pyroglutamate-modified A beta (A beta(pE)) peptides are particularly associated with cytotoxicity in Alzheimer's disease (AD). They represent the dominant fraction of A beta 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 beta(pE) plaques precedes the formation of plaques of full-length A beta (A beta(1.40/42)). Most of these properties appear to be associated with the higher hydrophobicity of A beta(pE) as well as an increased resistance to enzymatic degradation. However, the important question of whether A beta(pE) peptides induce pore activity in lipid membranes and their potential toxicity compared with other A beta pores is still open. Here we examine the activity of A beta(pE) pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that A beta(pE) pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the A beta family. However, there are also some significant differences. The onset of A beta(pE3-42) pore activity is generally delayed compared with A beta(1-42) pores. However, once formed, A beta(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 beta(pE) peptides induces a change in the conformation of the N-terminal strands of the A beta(pE3-42) pores. While the N-termini of wild-type A beta(1-42) peptides normally reside in the bulk water region, the N-termini of A beta(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 beta(pE) peptides.