Macrocyclic Peptides Derived from Familial Alzheimer's Disease Mutants Show Charge-Dependent Oligomeric Assembly and Toxicity.

Abstract

This work probes the role of charge in the oligomeric assembly, toxicity, and membrane destabilization of a series of peptides derived from Aβ and the E22Q and E22K familial mutants. In the mutant Aβ peptides, an acidic residue (E) is replaced with either a neutral or basic residue (Q or K), thus altering the net charge of the peptide. Acetylation at peripheral positions permits modulation of charge of the peptides and allows investigation of the role of charge in their oligomeric assembly, cytotoxicity, and membrane disruption. Peptides with the same net charge generally behave similarly even if the amino acid residue at position 22 differs. As the net charge of the peptide decreases, so does the extent of assembly, cytotoxicity, and membrane destabilization, which were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lactate dehydrogenase (LDH)-release assays with SH-SY5Y cells, and dye leakage assays using liposomes. These findings suggest that the charge of the amino acid side chain, rather than its size or hydrophobicity, accounts for the differences in the oligomeric assembly and toxicity of the E22 familial mutants of Aβ.