Toxicity of pyroglutaminated amyloid beta-peptides 3(pE)-40 and -42 is similar to that of A beta1-40 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 beta3(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 beta3(pE)-x isoforms may aggregate more rapidly and become more toxic than corresponding Abeta1-x peptides. However, the toxicity and aggregation properties of A beta3(pE)-42 and A beta3(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 microM A beta3(pE)-42 was similar to that of A beta1-42. Moreover, the toxicity of A beta3(pE)-40 paralleled that induced by A beta1-40 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 beta1-42, A beta3(pE)-42, A beta3(pE)-40, and A beta1-40 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.
Tekirian
T L
TL
Sanders-Brown Alzheimer's Disease Research Center and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Yang
A Y
AY
Glabe
C
C
Geddes
J W
JW
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D006624:Hippocampus / Q000166:cytology*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)