Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease

Fonseca, María Isabel; Ager, Rahasson R.; Chu, Shu Hui; Yazan, Ozkan; Sanderson, Sam D.; LaFerla, Frank M.; Taylor, Stephen M.; Woodruff, Trent M.; Tenner, Andrea J.

doi:10.4049/jimmunol.0901005

Cited by 243 publications

(289 citation statements)

References 70 publications

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“…This exclusivity leaves further discussion of other important factors involved in AD pathogenesis to another review. These include components of the complement system and many other factors [101][102][103] that doubtless contribute to such pathogenesis and are deserving of a more sharply focused discussion.…”

Section: Gene Polymorphisms As Risk Factors For Development Of Alzheimentioning

confidence: 99%

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Griffin¹,

Barger²

2010

US Neurology

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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis wasproposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each. KeywordsAlzheimer's disease (AD), amyloid β (Aβ), apolipoprotein E (ApoE), β−amyloid precursor protein (βAPP), cytokines, Down syndrome (DS), excitotoxicity, glutamate, interleukin-1 (IL-1), S100B, tumor necrosis factor alpha (TNFα) Disclosure: The authors have no conflicts of interest to declare. Acknowledgments:Much of the work cited in this article was supported by National Institutes of Health (NIH) grants P01AG12411 (to WSTG) and R01AG17498 (to SWB). The authors thank Orwa Aboud, MD, for helpful comments and editing. A progression of these neuropathological events seems apparent. For example, the plethora of Aβ plaques at end stages-from several to many-and an inclusion of neurofibrillary tangles-in a few to numerous neurons-strongly suggests that these neuropathological Received

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Section: Gene Polymorphisms As Risk Factors For Development Of Alzheimentioning

confidence: 99%

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Griffin¹,

Barger²

2010

US Neurology

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“…In different mouse models for AD the proinflammatory complement factor C5a and its receptor have been found to be upregulated in microglia in the immediate surroundings of cerebral amyloid plaques [35]. Fonseca et al demonstrated that the treatment with an antagonist of C5aR (PMX205) resulted in a reduction of pathological markers and improved memory skills in two different mouse models of AD [36]. In our previous study we showed that immunization against the proinflammatory complement factor C5a by AFF1 vaccine is able to interfere with microglia activation and thus neuropathology in Tg2576 mice, a model of AD [37].…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Vaccine against Complement Factor C5a and Amyloid Beta: A New Therapeutic Approach in Alzheimers Disease

linger¹,

Mihailovska²,

M³

et al. 2017

J Clin Cell Immunol

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by neuronal loss due to amyloid beta (Aβ) aggregations, neurofibrillary tangles, and prominent neuroinflammation. Inflammatory processes in AD primarily occur in response to misfolded and aggregated proteins, or mislocalized nucleic acids and reactive microglia. Prolonged chronic neuroinflammation is thought to reinforce neuronal cell dysfunction and cell death. In our previous study we demonstrated that the interference with the pro-inflammatory mediator C5a by AFF1 vaccine at an early stage of disease is able to reduce microglia activation and amyloid plaque burden which is accompanied by ameliorated memory deficiency in Tg2576 mice, a mouse model of AD. In a follow-up study we tested the effect of a combinatorial vaccine targeting neuroinflammation by C5a and Aβ aggregates, two detrimental processes in AD. The amyloid plaque burden in the brain of Tg2576 mice was significantly reduced upon vaccination by the monovalent anti-C5a (AFF1) as well as anti-Aβ (AD02) vaccine, however, the combinatorial AFF1/AD02 vaccine showed a clear additive beneficial effect. Moreover, contextual memory in Tg2576 mice was significantly improved by the combinatorial AFF1/AD02 vaccine when compared to monovalent or control vaccines. Thus, targeting two neuropathological processes such as neuroinflammation and Aβ aggregation may represent a new and promising approach for the treatment of AD.

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“…The reduction in pathology was correlative with improvements in contextual memory (Fonseca et al, 2009). CD88 is also up-regulated in the striatum of HD patients when compared with tissue from non-HD individuals (Singhrao et al, 1999).…”

Section: Role Of C5a In Cns Diseasesmentioning

confidence: 81%

“…In particular, CD88 activation seemed to be the driver of CNS pathology in numerous neurodegenerative diseases including AD, HD and ALS (Farkas et al, 2003, Fonseca et al, 2009, Fonseca et al, 2013, Singhrao et al, 1999, Woodruff et al, 2006, Woodruff et al, 2008a, Humayun et al, 2009). This was demonstrated by increased CD88 expression in human tissue and protection in animal models using a specific CD88 antagonist PMX205 (Fonseca et al, 2009, Woodruff et al, 2006, Woodruff et al, 2008a). …”

Section: Role Of C5a In Cns Diseasesmentioning

confidence: 99%

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The role of complement system in amyotrophic lateral sclerosis

Lee¹

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There is increasing evidence that neuro-inflammation drives disease progression in many neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS). Components of the innate immune complement system have been implicated in the pathogenesis of ALS. Within the complement signalling cascade C3a and C5a are regarded as potent inflammatory and immunomodulatory peptides with various biological functions. In the CNS their functions include chemotaxis and proliferation of microglia and astrocytes; generation of superoxide radicals; and induction of pro-inflammatory cytokine synthesis -all thought to be achieved via their main signalling receptors C3aR and CD88. Some of these functions have been observed in neurodegenerative disease, suggesting that these complement factors may play a role in ALS pathogenesis. However a comprehensive examination of complement expression and function of C3aR and CD88 in this disease has not been performed.The initial aim of this thesis was to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5, CD88 and C3aR) and regulators (CD55 and CD59a) in the lumbar spinal cord of the transgenic hSOD1 G93A mouse model of ALS. This was conducted during distinct disease stages, which were defined in this thesis. We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1 G93A mice. CD88 and C3aR was also increased during disease progression, with immunolocalization demonstrating expression on motor neurons and increasing expression of CD88 on microglia and increasing expression of C3aR on astrocytes surrounding the regions of motor neuron death.Our previous studies have demonstrated that hSOD1 G93A rats treated with the selective CD88 antagonist PMX205 had reduced gliosis and improvements in behavioural deficits, consistent with reduced neuropathology; suggesting CD88 has a pathogenic function in ALS. However, the contribution of C3aR to disease progression in ALS is still unknown. This thesis therefore next aimed to confirm the function of CD88, and determine the function of C3aR, in the disease progression of ALS in hSOD1 G93A mice. The function of CD88 signalling was investigated using two different approaches (pharmacological and genetic). Inhibition of CD88 using PMX205 (pharmacological approach) or hSOD1 G93A mice lacking CD88 (genetic approach) showed similarly extended survival when compared to vehicle and hSOD1 G93A mice. There was also a reduction in microglia, monocytes and cytokines (TNFα and IL-1β) transcripts in the spinal cord at the end-stage of disease. Taken together these results indicate that inhibition of CD88 significantly attenuates III disease progression potentially by reducing microglia/monocyte activation...

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Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease

Cited by 243 publications

References 70 publications

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Combinatorial Vaccine against Complement Factor C5a and Amyloid Beta: A New Therapeutic Approach in Alzheimers Disease

The role of complement system in amyotrophic lateral sclerosis

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