A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice

DeMattos, Ronald B.; Lu, Jirong; Tang, Ying; Racke, Margaret M.; DeLong, Cindy A.; Tzaferis, John A.; Hole, Justin T.; Forster, Beth M.; McDonnell, Peter C.; Liu, Feng; Kinley, Robert D.; Jordan, William H.; Hutton, Michael L.

doi:10.1016/j.neuron.2012.10.029

Cited by 442Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice

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DeMattos, Ronald B., Lu, Jirong, Tang, Ying, Racke, Margaret M., DeLong, Cindy A., Tzaferis, John A., Hole, Justin T., Forster, Beth M. +5 more·2012·Neuron

DOI 10.1016/j.neuron.2012.10.029

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Abstract

Aβ Immunotherapy is a promising therapeutic approach for Alzheimer's disease. Preclinical studies demonstrate that plaque prevention is possible; however, the more relevant therapeutic removal of existing plaque has proven elusive. Monoclonal antibodies in development target both soluble and insoluble Aβ peptide. We hypothesized that antibody specificity for deposited plaque was critical for plaque removal since soluble Aβ peptide would block recognition of deposited forms. We developed a plaque-specific antibody that targets a modified Aβ peptide (Aβ(p3-42)), which showed robust clearance of pre-existing plaque without causing microhemorrhage. Interestingly, a comparator N-terminal Aβ antibody 3D6, which binds both soluble and insoluble Aβ(1-42), lacked efficacy for lowering existing plaque but manifested a significant microhemorrhage liability. Mechanistic studies suggested that the lack of efficacy for 3D6 was attributed to poor target engagement in plaques. These studies have profound implications for the development of therapeutic Aβ antibodies for Alzheimer's disease.

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Donanemab is a humanized mAb specific for N-terminally pyroglutamate-modified Aβ proteins found in amyloid plaques and aids plaque removal through microglial-mediated phagocytosis.
“This mAb is specific for the N-terminally, pyroglutamate-modified Aβ proteins found in amyloid plaques and aids plaque removal through microglial-mediated phagocytosis.”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [67]
Microglial-mediated phagocytosis is one of the major mechanisms for removal of plaques in response to some anti-Aβ antibodies.
“One of the major mechanisms for removal of the plaques in response to some anti-A␤ antibodies is microglial-mediated phagocytosis (Bard et al., 2000;Demattos et al., 2012).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Demattos et al., 2012
The soluble equilibrium mechanism of Aβ immunotherapy includes antibodies neutralising and solubilising the Aβ plaque both centrally and peripherally.
“The soluble equilibrium mechanism includes antibodies neutralising and solubilising the Aβ plaque both centrally and peripherally.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [117]
Antibodies bind to amyloid seed in the initial stages and can prevent its propagation.
“Antibodies also bind to Amyloid seed in the initial stages and can prevent its propagation [117].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [117]
The phagocytosis mechanism of Aβ immunotherapy is based on opsonisation of Aβ plaque, which stimulates microglia-associated phagocytosis.
“Phagocytosis mechanism is based on opsonisation of Aβ plaque which stimulates microglia associated phagocytosis.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [117]

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Authors: DeMattos, R. B., Lu, J., Tang, Y., Racke, M. M., DeLong, C. A., Tzaferis, J. A., Hole, J. T., Forster, B. M., McDonnell, P. C., Liu, F., Kinley, R. D., Jordan, W. H., & Hutton, M. L.
Affiliations: Eli Lilly (United States) (US)
Corresponding author: DeMattos, Ronald B.
ORCID: DeMattos, Ronald B.
Lu, Jirong
Tang, Ying
Liu, Feng
Venue: Neuron
Publisher: Elsevier BV
Published: 2012-12
Volume: 76
Issue: 5
Pages: 908-920
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2012.10.029
OpenAlex: W2024917017
Cited by: 442
References: 55
Citations by year: 2026: 39 · 2025: 57 · 2024: 68 · 2023: 49 · 2022: 28 · 2021: 29 · 2020: 36 · 2019: 11 · 2018: 17 · 2017: 18 · 2016: 23 · 2015: 19 · 2014: 29 · 2013: 18 · 2012: 1
FWCI: 14.36
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
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: Alzheimer's disease, amyloid plaques, monoclonal antibodies, amyloid-beta 42, antibody specificity, plaque clearance, microhemorrhages, target engagement, mouse model
MeSH terms: Age Factors, Alzheimer Disease, Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Hemorrhage, Hippocampus, Humans, Immunoglobulin G, Immunotherapy, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Plaque, Amyloid

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A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice

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