Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease
Open accessAbstract
Alzheimer’s disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2–3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49–62%) and activated glia (42–68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.
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The 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].”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [89]
The Discussion (page not provided) reports less neuropathology in a C1q-knockout Alzheimer’s mouse model and accelerated pathology in C3-deficient models, supporting the claim that complement deficiency has had differing effects. This paper tested a C5aR antagonist, not C5aR deficiency, and the cited passages do not establish outcomes for C3ar1 or Cd59 deficiency. (LLM, conf=0.87)
Experimental — accuracy not yet measuredStudies manipulating the complement system have yielded mixed results.
“Further, studies manipulating the complement system have yielded mixed results.”
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 [124]
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 [124]
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 [124]
C5aR antagonism reduced the extent of tau pathology.
“C3 inhibition by transgenic expression of a soluble form of the mouse complement inhibitory protein Crry (Britschgi et al., 2012) or C5aR antagonism (Fonseca et al., 2009) reduced the extent of tau pathology.”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Fonseca et al., 2009
Inhibition of C5a using a C5aR antagonist resulted in rescue of a hippocampal-dependent memory task.
“Inhibition of C5a, a C3 downstream activation fragment, using a C5aR antagonist resulted in rescue of a hippocampal-dependent memory task (24).”
From Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice (2017) · cites this paper as [24]
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- Authors
- Fonseca, M. I., Ager, R. R., Chu, S.-H., Yazan, O., Sanderson, S. D., LaFerla, F. M., Taylor, S. M., Woodruff, T. M., & Tenner, A. J.
- Affiliations
- University of California, Irvine (US)
- School of Allied Health Professions, University of Nebraska , Omaha, NE 68198
- The University of Queensland (AU)
- Corresponding author
- Yazan, Ozkan
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-07
- Volume
- 183
- Issue
- 2
- Pages
- 1375-1383
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4067320
- OpenAlex
- W2155172987
- Cited by
- 268
- References
- 73
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 15 · 2020: 17 · 2019: 14 · 2018: 20 · 2017: 16 · 2016: 7 · 2015: 10 · 2014: 12 · 2013: 18 · 2012: 18
- FWCI
- 11.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of California, Irvine
- National Institute on Aging (P01AG000538, P50 AG-00538)
- National Institute of Neurological Disorders and Stroke (T32NS007444, R01NS035144, NS35144, NS-007444)
- 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
- Alzheimer's disease, C5a receptor antagonist, PMX205, complement system, C5a, neuroinflammation, amyloid plaques, hyperphosphorylated tau, microglial activation, astrocytes, Tg2576 mice, 3xTg-AD mice, cognitive function, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Inflammation, Nerve Degeneration, Neuroglia, Peptides, Cyclic, Personality Disorders, Receptors, Complement, Neurofibrillary Tangles, Receptor, Anaphylatoxin C5a, Mice, Plaque, Amyloid
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