Monoclonal antibodies that target pathological assemblies of Abeta.
Amyloid beta (Abeta) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Abeta oligomers (amyloid beta-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Abeta oligomers and fibrils but not the physiologically prevalent Abeta monomer. Discrimination derived from an epitope found in assemblies of Abeta1-28 and ADDLs but not in other sequences, including Abeta1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Abeta assemblies, these antibodies provide tools by which pathological Abeta assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.
Lambert
Mary P
MP
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Velasco
Pauline T
PT
Chang
Lei
L
Viola
Kirsten L
KL
Fernandez
Sara
S
Lacor
Pascale N
PN
Khuon
Daliya
D
Gong
Yuesong
Y
Bigio
Eileen H
EH
Shaw
Pamela
P
De Felice
Fernanda G
FG
Krafft
Grant A
GA
Klein
William L
WL
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D000918:Antibody Specificity; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D000099291:Adducins
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D002148:Calmodulin-Binding Proteins; D000939:Epitopes; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C102021:ADD3 protein, human; D000099291:Adducins; C022616:thiazolyl blue