Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers.
Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A beta peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A beta(1-11) antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A beta(1-11) antibody prevented aggregation of A beta(42) and induced disaggregation of preformed A beta(42) fibrils down to nonfilamentous and nontoxic species. Anti-A beta(1-11) antibody delayed A beta(42) oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A beta oligomers with the anti-A beta(1-11) antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology.
Mamikonyan
Grigor
G
Department of Immunology, The Institute for Molecular Medicine, Huntington Beach, California 92647, USA.
Necula
Mihaela
M
Mkrtichyan
Mikayel
M
Ghochikyan
Anahit
A
Petrushina
Irina
I
Movsesyan
Nina
N
Mina
Erene
E
Kiyatkin
Anatoly
A
Glabe
Charles G
CG
Cribbs
David H
DH
Agadjanyan
Michael G
MG
D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D001921:Brain / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008968:Molecular Conformation; D011485:Protein Binding; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016207:Cytokines; D000939:Epitopes