Monoclonal antibodies that target pathological assemblies of Aβ
Abstract
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…
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The generation, purification, and characterization of A11, OC, and NU-4 antibodies have been described previously.
“Generation, purification, and characterization of A11, OC, and NU-4 have been described previously.70,71”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [71]
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“…(1:100, Invitrogen, Grand Island, NY); NU4, an antibody raised against Abderived diffusible ligands that preferentially binds Ab oligomers over monomers (Lambert et al., 2007) (1:2,000, gift from Dr. William Klein, Northwestern University, Evanston, IL); Alz50, a mouse IgM raised against amino…”
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Self-citation
- Authors
- Lambert, M. P., Velasco, P. T., Chang, L., Viola, K. L., Fernandez, S., Lacor, P. N., Khuon, D., Gong, Y., Bigio, E. H., Shaw, P., De Felice, F. G., Krafft, G. A., & Klein, W. L.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Klein, William L.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2006-08-21
- Volume
- 100
- Issue
- 1
- Pages
- 23-35
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2078212921
- Cited by
- 314
- References
- 17
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 13 · 2022: 14 · 2021: 14 · 2020: 12 · 2019: 14 · 2018: 15 · 2017: 12 · 2016: 14 · 2015: 20 · 2014: 25 · 2013: 14 · 2012: 28
- FWCI
- 13.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Southern California
- Northwestern University
- National Institutes of Health
- National Institute on Aging (R01 AG11385, AG 22547, P30AG13854, R01AG022547, R01AG011385, R01-AG18877, P30AG013854, R01AG018877)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta oligomers, monoclonal antibodies, Alzheimer's disease, immunoneutralization, reactive oxygen species, therapeutic antibodies, amyloid fibrils
- MeSH terms
- Adducins, Alzheimer Disease, Animals, Antibodies, Monoclonal, Antibody Specificity, Epitopes, Brain, Calmodulin-Binding Proteins, Cells, Cultured, Dose-Response Relationship, Drug, Glial Fibrillary Acidic Protein, Humans, Immunohistochemistry, Neurons, Peptide Fragments, Protein Binding, Rabbits, Tetrazolium Salts, Thiazoles, Immunoblotting, Amyloid beta-Peptides, Reactive Oxygen Species, Mice
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