Toxicity of pyroglutaminated amyloid β-peptides 3(pE)-40 and-42 is similar to that of Aβ1-40 and-42

An N-terminal truncated isoform of the amyloid beta-peptide (A beta) that begins with a pyroglutamate (pE) residue at position 3 [A beta 3(pE)-42] is the predominant isoform found in senile plaques. Based upon previous in vitro studies regarding A beta N-terminal truncated isoforms, it has been hypothesized that A beta S(pE)-x isoforms may aggregate more rapidly and become more toxic than corresponding A beta 1-x peptides, However, the toxicity and aggregation properties of A beta 3(pE)-42 and A beta 3(pE)-40 have not previously been examined. After initial solubilization and 1-week preaggregation of each peptide at 37 degrees C and pH 7.4, the toxicity of 5-50 mu M A beta 3(pE)-42 was similar to that of A beta 1-42. Moreover, the toxicity of A beta 3(pE)-40 paralleled that induced by A beta 1-40 in both 1 day in vitro (DIV) cortical and 7 DIV hippocampal cells. Circular dichroism spectra did not reveal major differences in secondary structure between aged A beta 1-42, A beta 3(pE)-42, A beta 3(pE)-40, and A beta 1-40 or freshly solubilized forms of these peptides. Overall, the data indicate that the loss of the two N-terminal amino acids and the cyclization of glutamate at position 3 do not alter the extracellular toxicity of A beta.