New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease
Open accessAbstract
There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (FcγR) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking FcγR by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that FcγR expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of FcγR in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of FcγR in the healthy and diseased brain. Here we review the literature on FcγR expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy.
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In mouse macrophages and COS cells, SHIP1 activates the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis.
“In mouse macrophages and COS cells, SHIP1 was shown to activate the ITIM of the inhibitory receptor FCγRIIβ, which inhibits the activating receptor FCγRIIA to block FCγRIIA-mediated phagocytosis (Fig. 3C).”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [139]
The Fc receptors section and Figure 1B describe FcγRIIb-mediated inhibition of activating-receptor signaling. But they give the opposite sequence for SHIP1: ITIM phosphorylation recruits SHIP1, rather than SHIP1 activating the ITIM. They do not report an experiment in mouse macrophages or COS cells showing blockade of FcγRIIa-mediated phagocytosis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSHIP1 directly inhibits FCγRIIA by binding to its ITAM, which prevents activation of PI3K.
“SHIP1 also was shown to directly inhibit FCγRIIA by binding to its ITAM (Fig. 3C), which prevents the activation of PI3K [134, 137–140].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [139]
The Fc receptors section (Figure 1 caption; page unavailable) says SHIP1 inhibits downstream PI3K signaling. It describes SHIP1 as recruited following phosphorylation of an inhibitory receptor’s ITIM, not as directly binding the ITAM of activating FcγRIIa, and does not say it prevents PI3K activation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTherapeutics relying on IgG antibodies, if administered excessively, might induce aging-related defects.
“our results raise a caution that therapeutics relying on IgG antibodies, if administered excessively, might induce aging-related defects.”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [76]
The Abstract and Conclusions warn that therapeutic antibodies may cause CNS vascular damage and exacerbate neurodegeneration through FcγR activation. The paper does not say that excessive administration induces aging-related defects generally; its discussion concerns potential harms of CNS immunotherapy, particularly in the context of Alzheimer’s disease. (LLM, conf=0.83)
Experimental — accuracy not yet measuredFCγR activation promotes Aβ clearance via phagocytosis.
“FCγR activation also promotes Aβ clearance via phagocytosis [139, 140].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [139]
Binding of Fc receptors is known to activate microglia and stimulate release of proinflammatory molecules which can exacerbate the degenerative process.
“However, binding of Fc receptors is also known to activate microglia and stimulate release of proinflammatory molecules which can exacerbate the degenerative process [182].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [182]
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“, 2008), Fc receptors (Fuller et al., 2014), Ig-superfamily receptors including TREM2 (Ulrich et al.”
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- Authors
- Fuller, J. P., Stavenhagen, J. B., & Teeling, J. L.
- Affiliations
- University of Southampton (GB)
- Lundbeck (Denmark) (DK)
- Corresponding author
- Fuller, James P.
- ORCID
- Teeling, Jessica L.
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-08-21
- Volume
- 8
- Pages
- 235-235
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC4139653
- OpenAlex
- W2168804892
- Cited by
- 154
- References
- 86
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 15 · 2023: 22 · 2022: 18 · 2021: 11 · 2020: 12 · 2019: 15 · 2018: 11 · 2017: 6 · 2016: 12 · 2015: 8 · 2014: 2
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- Fc gamma receptor, Alzheimer's disease, immunotherapy, amyloid-beta, anti-amyloid antibodies, neurodegeneration, microglia, vascular injury, neuroinflammation, age-related neurodegenerative diseases, therapeutic antibodies, antibody engineering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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