Immunodominant epitope and properties of pyroglutamate-modified Abeta-specific antibodies produced in rabbits.
N-truncated and N-modified forms of amyloid beta (Abeta) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as transgenic mouse models of AD. Although the pathological significance of these shortened forms Abeta is not completely understood, previous studies have demonstrated that these peptides are significantly more resistant to degradation, aggregate more rapidly in vitro and exhibit similar or, in some cases, increased toxicity in hippocampal neuronal cultures compared to the full length peptides. In the present study we further investigated the mechanisms of toxicity of one of the most abundant N-truncated/modified Abeta peptide bearing amino-terminal pyroglutamate at position 3 (AbetaN3(pE)). We demonstrated that AbetaN3(pE) oligomers induce phosphatidyl serine externalization and membrane damage in SH-SY5Y cells. Also, we produced AbetaN3(pE)-specific polyclonal antibodies in rabbit and identified an immunodominant epitope recognized by anti-AbetaN3(pE) antibodies. Our results are important for developing new immunotherapeutic compounds specifically targeting AbetaN3(pE) aggregates since the most commonly used immunogens in the majority of vaccines for AD have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Abeta, which is absent in N-amino truncated peptides.
Acero
G
G
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), AP 70228, Cuidad Universitaria, México DF, 04510, Mexico.
Manoutcharian
K
K
Vasilevko
V
V
Munguia
M E
ME
Govezensky
T
T
Coronas
G
G
Luz-Madrigal
A
A
Cribbs
D H
DH
Gevorkian
G
G
D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D023582:Alzheimer Vaccines / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000633:toxicity; D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology; D000918:Antibody Specificity / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D015394:Molecular Structure; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D010718:Phosphatidylserines / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry / Q000276:immunology*; D011817:Rabbits
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies; D016056:Immunodominant Epitopes; D010455:Peptides; D010718:Phosphatidylserines; D011761:Pyrrolidonecarboxylic Acid