Activity and architecture of pyroglutamate-modified amyloid-β (Aβ_pE3-42) pores

Among the family of Aβ peptides, pyroglutamate-modified Aβ (Aβ_pE) peptides are particularly associated with cytotoxicity in Alzheimers disease (AD). They represent the dominant fraction of Aβ oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of Aβ_pE plaques precedes the formation of plaques of full-length Aβ (Aβ_1-40/42). Most of these properties appear to be associated with the higher hydrophobicity of Aβ_pE as well as an increased resistance to enzymatic degradation. However, the important question of whether Aβ_pE peptides induce pore activity in lipid membranes and their potential toxicity compared with other Aβ pores is still open. Here we examine the activity of Aβ_pE pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that Aβ_pE pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the Aβ family. However, there are also some significant differences. The onset of Aβ _pE3-42 pore activity is generally delayed compared with Aβ_1-42 pores. However, once formed, Aβ_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 Aβ_pE peptides induces a change in the conformation of the N-terminal strands of the Aβ_pE3-42 pores. While the N-termini of wild-type Aβ_1-42 peptides normally reside in the bulk water region, the N-termini of Aβ_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 Aβ_pE peptides.