Non-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid-β In Vivo by Immunotherapy
Open accessAbstract
Transgenic (Tg) mouse models overexpressing amyloid precursor protein (APP) develop senile plaques similar to those found in Alzheimer's disease in an age-dependent manner. Recent reports demonstrated that immunotherapy is effective at preventing or removing amyloid-beta deposits in the mouse models. To characterize the mechanisms involved in clearance, we used antibodies of either IgG1 (10d5) or IgG2b (3d6) applied directly to the brains of 18-month-old Tg2576 or 20-month-old PDAPP mice. Both 10d5 and 3d6 led to clearance of 50% of diffuse amyloid deposits in both animal models within 3 d. Fc receptor-mediated clearance has been shown to be important in an ex vivo assay showing antibody-mediated clearance of plaques by microglia. We now show, using in vivo multiphoton microscopy, that FITC-labeled F(ab')2 fragments of 3d6 (which lack the Fc region of the antibody) also led to clearance of 45% of the deposits within 3 d, similar to the results obtained with full-length 3d6 antibody. This result suggests that direct disruption of plaques, in addition to Fc-dependent phagocytosis, is involved in the antibody-mediated clearance of amyloid-beta deposits in vivo. Dense-core deposits that were not cleared were reduced in size by approximately 30% with full-length antibodies and F(ab')2 fragments 3 d after a topical treatment. Together, these results indicate that clearance of amyloid deposits in vivo may involve, in addition to Fc-dependent clearance, a non-Fc-mediated disruption of plaque structure.
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Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid to suggesting that microglia play no role in the control of amyloid deposition.
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Bacskai et al., 2002
The Results report in vivo clearance of dense-core amyloid plaques after antibody treatment, and the Discussion treats microglial phagocytosis as a possible clearance mechanism. But the paper attributes direct evidence of microglial phagocytosis to ex vivo work; its own in vivo experiments also found effective Fc-independent clearance. It therefore does not show that microglia phagocytosed fibrillar amyloid in vivo. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia may only be able to remove fibrillar amyloid from plaques during heightened levels of activation such as in injury models or after Aβ immunization.
“Thus microglia may only be able to remove fibrillar amyloid from plaques during heightened levels of activation such as in injury models (DiCarlo et al., 2001) or after Aβ immunization (Bacskai et al., 2002).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Bacskai et al., 2002
The introduction links microglial activation after topical antibody treatment to a possible Fc-mediated clearance mechanism, and the Results report clearance of some dense-core plaques after antibody treatment. But the paper does not establish that microglia themselves cleared those plaques or that heightened activation is required; it also finds evidence for non-Fc-mediated clearance. Its experiments used topical antibodies, not Aβ immunization. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTreatment with anti-Aβ antibodies in APP transgenic mice can remove plaques.
“treatment with anti-A antibodies in APP transgenic mice can remove plaques (Bacskai et al., 2002)”
From Dendritic Spine Abnormalities in Amyloid Precursor Protein Transgenic Mice Demonstrated by Gene Transfer and Intravital Multiphoton Microscopy (2005) · cites this paper as Bacskai et al., 2002
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- Authors
- Bacskai, B. J., Kajdasz, S. T., McLellan, M. E., Games, D., Seubert, P., Schenk, D., & Hyman, B. T.
- Affiliations
- Massachusetts General Hospital (US)
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-09-15
- Volume
- 22
- Issue
- 18
- Pages
- 7873-7878
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758112
- OpenAlex
- W1528113046
- Cited by
- 323
- References
- 3
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 8 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 14 · 2013: 10 · 2012: 22
- FWCI
- 16.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fidelity Foundation
- National Institute on Aging (AG-08487, P01AG15453, R01AG008487, P01AG015453)
- National Institute of General Medical Sciences (T32 GM07753, T32GM007753)
- 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 clearance, antibody immunotherapy, F(ab')2 fragments, Fc receptors, Alzheimer's disease, amyloid plaques, Tg2576 mice, PDAPP mice, plaque disruption, microglial phagocytosis
- MeSH terms
- Administration, Topical, Alzheimer Disease, Animals, Antibodies, Brain, Disease Models, Animal, Fluorescent Dyes, Humans, Immunoglobulin Fab Fragments, Immunoglobulin Fc Fragments, Immunotherapy, Mice, Transgenic, Microscopy, Fluorescence, Mutation, Phagocytosis, Thiazoles, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Benzothiazoles, Plaque, Amyloid
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