Complement C3 Deficiency Leads to Accelerated Amyloid Plaque Deposition and Neurodegeneration and Modulation of the Microglia/Macrophage Phenotype in Amyloid Precursor Protein Transgenic Mice
Open accessAbstract
Complement factor C3 is the central component of the complement system and a key inflammatory protein activated in Alzheimer's disease (AD). Previous studies demonstrated that inhibition of C3 by overexpression of soluble complement receptor-related protein y in an AD mouse model led to reduced microgliosis, increased amyloid beta (Abeta) plaque burden, and neurodegeneration. To further address the role of C3 in AD pathology, we generated a complement C3-deficient amyloid precursor protein (APP) transgenic AD mouse model (APP;C3(-/-)). Brains were analyzed at 8, 12, and 17 months of age by immunohistochemical and biochemical methods and compared with age-matched APP transgenic mice. At younger ages (8-12 months), no significant neuropathological differences were observed between the two transgenic lines. In contrast, at 17 months of age, APP;C3(-/-) mice showed significant changes of up to twofold increased total Abeta and fibrillar amyloid plaque burden in midfrontal cortex and hippocampus, which correlated with (1) significantly increased Tris-buffered saline (TBS)-insoluble Abeta(42) levels and reduced TBS-soluble Abeta(42) and Abeta(40) levels in brain homogenates, (2) a trend for increased Abeta levels in the plasma, (3) a significant loss of neuronal-specific nuclear protein-positive neurons in the hippocampus, and (4) differential activation of microglia toward a more alternative phenotype (e.g., significantly increased CD45-positive microglia, increased brain levels of interleukins 4 and 10, and reduced levels of CD68, F4/80, inducible nitric oxide synthase, and tumor necrosis factor). Our results suggest a beneficial role for complement C3 in plaque clearance and neuronal health as well as in modulation of the microglia phenotype.
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Altering the proliferation, signaling, and migration of microglia directly impacts development of Aβ pathology.
“numerous other studies have suggested that altering the proliferation, 58 signaling, 8,9,11 and migration 7,59 of microglia directly impact development of A pathology.”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [11]
The Results and Discussion report that C3-deficient APP mice had increased Aβ plaque burden and an altered microglia/macrophage activation phenotype, supporting an association between altered complement signaling and Aβ pathology. The study did not selectively alter microglial signaling or establish that the microglial change directly caused the plaque increase; the Discussion presents impaired phagocytosis as a possible explanation. The proliferation and migration clauses have separate citations and are not assessed against this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe deficiency of complement factors such as C1q, C3, C3ar1, C5aR, and Cd59, has exacerbated neuropathology in some studies and reduced neuropathology in others.
“The deficiency of complement factors such as C1q, C3, C3ar1, C5aR, and Cd59, has exacerbated neuropathology in some studies [84–86] and reduced neuropathology in others [87–89].”
Studies manipulating the complement system have yielded mixed results.
“Further, studies manipulating the complement system have yielded mixed results.”
In a mouse model of Alzheimer's disease, overexpression of CRRY, C3 deficiency, or blocking C5a increases amyloid-beta levels without increased production, reflecting the role of complement in microglial phagocytosis.
“In a mouse model of AD, overexpression of soluble complement component 3b/4b receptor 1-like (CRRY; a complement inhibitor in rodents) (122), C3 deficiency (123), or blocking of C5a (124), a downstream component of the complement cascade, increased Aβ levels in the absence of increased Aβ production, reflecting the role of complement in microglial phagocytosis.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [123]
Inhibition of different complement components impairs amyloid-beta phagocytosis and results in elevated synapse loss.
“other studies have reported that inhibition of different components of complement impaired Aβ phagocytosis, resulting in elevated synapse loss.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [123]
Complement blockade is associated with increased neurodegeneration.
“In the same studies, complement blockade was associated with increased neurodegeneration.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [123]
C3 knockout or inhibition appears to increase amyloid burden.
“though it appears to increase amyloid burden (Wyss-Coray et al., 2002; Maier et al., 2008; Shi et al., 2017a).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Maier et al., 2008
Aged C3-deficient J20 hAPP transgenic mice had a higher plaque load, slightly reduced neuron number, and altered macrophage polarization compared to age-matched J20 mice.
“We previously reported that aged C3-deficient J20 hAPP transgenic mice had a higher plaque load, slightly reduced neuron number, and altered macrophage polarization compared to age-matched J20 mice (21).”
From Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice (2017) · cites this paper as [21]
C3 inhibition enhances plaque deposition and promotes neurodegeneration in J20 hAPP mice.
“C3 inhibition enhanced plaque deposition and promoted neurodegeneration in J20 hAPP mice either by over-expression of sCrry (22) or genetic deletion of C3 (21).”
From Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice (2017) · cites this paper as [21]
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References 44 · Cited by 323
- Authors
- Maier, M., Peng, Y., Jiang, L., Seabrook, T. J., Carroll, M. C., & Lemere, C. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Lemere, C. A.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-06-18
- Volume
- 28
- Issue
- 25
- Pages
- 6333-6341
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3329761
- OpenAlex
- W2002774469
- Cited by
- 323
- References
- 44
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 25 · 2023: 12 · 2022: 20 · 2021: 25 · 2020: 15 · 2019: 23 · 2018: 19 · 2017: 14 · 2016: 13 · 2015: 19 · 2014: 12 · 2013: 13 · 2012: 26
- FWCI
- 13.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG020159, AG20159)
- National Institute of Neurological Disorders and Stroke (R01NS136122)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- complement C3, Alzheimer's disease, amyloid plaques, amyloid precursor protein transgenic mice, microglia phenotype, neurodegeneration, plaque clearance, hippocampus, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Complement C3, Humans, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Phenotype, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Plaque, Amyloid
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