Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies.
Oligomers of the beta-amyloid (Abeta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic Abeta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar Abeta peptide, enabling the generation of highly Abeta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar Abeta in various Abeta preparations. The globulomer-specific antibody A-887755 was able to prevent Abeta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with Abeta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of Abeta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.
Hillen
Heinz
H
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott, D-67061 Ludwigshafen, Germany. heinz.hillen@abbott.com
Barghorn
Stefan
S
Striebinger
Andreas
A
Labkovsky
Boris
B
Müller
Reinhold
R
Nimmrich
Volker
V
Nolte
Marc W
MW
Perez-Cruz
Claudia
C
van der Auwera
Ingrid
I
van Leuven
Fred
F
van Gaalen
Marcel
M
Bespalov
Anton Y
AY
Schoemaker
Hans
H
Sullivan
James P
JP
Ebert
Ulrich
U
D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000276:immunology; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal