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Active immunization against complement factor C5a: a new therapeutic approach for Alzheimer's disease.

Landlinger C, Oberleitner L, Gruber P, Noiges B, Yatsyk K, Santic R, Mandler M, Staffler G - J Neuroinflammation (2015)

Bottom Line: Especially, complement factor C5a and its receptor have been found to be up-regulated in microglia in the immediate surroundings of cerebral amyloid plaques and blocking of C5aR resulted in a reduction of pathological markers in a model of AD.Both C5a-targeting vaccines were highly immunogenic and induced sustained antibody titers against C5a.C5a-peptide vaccines represent a safe and well-tolerated immunotherapy, which is able to induce a strong and specific immune response against the pro-inflammatory molecule C5a.

View Article: PubMed Central - PubMed

Affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. christine.landlinger@affiris.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by neuronal loss due to amyloid beta aggregations, neurofibrillary tangles, and prominent neuroinflammation. Recently, interference with neuroinflammation as a new therapeutic approach for AD treatment gained great interest. Microglia cells, one of the major contributors in neuroinflammation, are activated in response to misfolded proteins such as amyloid β and cell debris leading to a sustained release of pro-inflammatory mediators. Especially, complement factor C5a and its receptor have been found to be up-regulated in microglia in the immediate surroundings of cerebral amyloid plaques and blocking of C5aR resulted in a reduction of pathological markers in a model of AD. Here, we investigate the effect of active vaccination against the complement factor C5a to interfere with neuroinflammation and neuropathologic alterations in a mouse model of AD.

Methods: Short antigenic peptides AFF1 and AFF2, which mimic a C-terminal epitope of C5a, were selected and formulated to vaccines. These vaccines are able to induce a highly specific antibody response to the target protein C5a. Tg2576 mice, a common model of AD, were immunized with these two C5a-peptide vaccines and the induced immune response toward C5a was analyzed by ELISA and Western blot analysis. The influence on memory retention was assessed by a contextual fear conditioning test. Microglia activation and amyloid plaque deposition in the brain was visualized by immunohistochemistry.

Results: Both C5a-targeting vaccines were highly immunogenic and induced sustained antibody titers against C5a. Tg2576 mice vaccinated at early stages of the disease showed significantly improved contextual memory accompanied by the reduction of microglia activation in the hippocampus and cerebral amyloid plaque load compared to control mice. Late-stage immunization also showed a decrease in the number of activated microglia, and improved memory function, however, had no influence on the amyloid β load.

Conclusion: C5a-peptide vaccines represent a safe and well-tolerated immunotherapy, which is able to induce a strong and specific immune response against the pro-inflammatory molecule C5a. In a mouse model of AD, C5a-peptide vaccines reduce microglia activation and thus neuroinflammation, which is supposed to lead to reduced neuronal dysfunction and AD symptomatic decline.

No MeSH data available.


Related in: MedlinePlus

Model of C5a-peptide vaccines interference with chronic, self-sustaining inflammatory processes in AD. APP processing to amyloid peptides (Aβ 1–42) is influenced by an unknown trigger. Aβ peptides start to aggregate in the brain and microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR) or by complement activation in the response to Aβ depositions leading to the formation of the pro-inflammatory molecule C5a. We propose that C5a-AFFITOPE® vaccines interfere with the pro-inflammatory molecule C5a thereby hindering enhanced microglia activation which leads to excessive release of pro-inflammatory mediators. These pro-inflammatory mediators provoke stress conditions, which in turn reinforce APP production and processing to amyloid peptides (Aβ 1–42). We believe that C5a-AFFITOPE® vaccines do have the capacity to interfere with chronic and self-sustaining inflammatory interactions between activated microglia, stressed neurons, and Aβ plaques which ultimately lead to neuronal cell death and cognitive decline in AD patients
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Fig8: Model of C5a-peptide vaccines interference with chronic, self-sustaining inflammatory processes in AD. APP processing to amyloid peptides (Aβ 1–42) is influenced by an unknown trigger. Aβ peptides start to aggregate in the brain and microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR) or by complement activation in the response to Aβ depositions leading to the formation of the pro-inflammatory molecule C5a. We propose that C5a-AFFITOPE® vaccines interfere with the pro-inflammatory molecule C5a thereby hindering enhanced microglia activation which leads to excessive release of pro-inflammatory mediators. These pro-inflammatory mediators provoke stress conditions, which in turn reinforce APP production and processing to amyloid peptides (Aβ 1–42). We believe that C5a-AFFITOPE® vaccines do have the capacity to interfere with chronic and self-sustaining inflammatory interactions between activated microglia, stressed neurons, and Aβ plaques which ultimately lead to neuronal cell death and cognitive decline in AD patients

Mentions: Activation of microglia by Aβ and complement is supposed to promote the excessive release of pro-inflammatory cytokines [32], chemokines [33, 34], and further complement components [35, 36], as well as the release of reactive oxygen and nitrogen species [37, 38], altogether leading to dysfunction and loss of synapse signaling [39]. Pro-inflammatory mediators provoke a number of stress conditions which, in turn, can enhance APP production and processing to amyloid peptides (Aβ 1–42) [40–45]. Thus, chronic and self-sustaining inflammatory interactions between the complement system, activated microglia, stressed neurons, and Aβ plaques occur, which ultimately lead to neuronal cell death and cognitive decline in AD patients. Our intention was to target the pro-inflammatory complement activation product C5a in order to interfere with enhanced microglia activation and sustained neuroinflammation in AD (Fig. 8).Fig. 8


Active immunization against complement factor C5a: a new therapeutic approach for Alzheimer's disease.

Landlinger C, Oberleitner L, Gruber P, Noiges B, Yatsyk K, Santic R, Mandler M, Staffler G - J Neuroinflammation (2015)

Model of C5a-peptide vaccines interference with chronic, self-sustaining inflammatory processes in AD. APP processing to amyloid peptides (Aβ 1–42) is influenced by an unknown trigger. Aβ peptides start to aggregate in the brain and microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR) or by complement activation in the response to Aβ depositions leading to the formation of the pro-inflammatory molecule C5a. We propose that C5a-AFFITOPE® vaccines interfere with the pro-inflammatory molecule C5a thereby hindering enhanced microglia activation which leads to excessive release of pro-inflammatory mediators. These pro-inflammatory mediators provoke stress conditions, which in turn reinforce APP production and processing to amyloid peptides (Aβ 1–42). We believe that C5a-AFFITOPE® vaccines do have the capacity to interfere with chronic and self-sustaining inflammatory interactions between activated microglia, stressed neurons, and Aβ plaques which ultimately lead to neuronal cell death and cognitive decline in AD patients
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4537556&req=5

Fig8: Model of C5a-peptide vaccines interference with chronic, self-sustaining inflammatory processes in AD. APP processing to amyloid peptides (Aβ 1–42) is influenced by an unknown trigger. Aβ peptides start to aggregate in the brain and microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR) or by complement activation in the response to Aβ depositions leading to the formation of the pro-inflammatory molecule C5a. We propose that C5a-AFFITOPE® vaccines interfere with the pro-inflammatory molecule C5a thereby hindering enhanced microglia activation which leads to excessive release of pro-inflammatory mediators. These pro-inflammatory mediators provoke stress conditions, which in turn reinforce APP production and processing to amyloid peptides (Aβ 1–42). We believe that C5a-AFFITOPE® vaccines do have the capacity to interfere with chronic and self-sustaining inflammatory interactions between activated microglia, stressed neurons, and Aβ plaques which ultimately lead to neuronal cell death and cognitive decline in AD patients
Mentions: Activation of microglia by Aβ and complement is supposed to promote the excessive release of pro-inflammatory cytokines [32], chemokines [33, 34], and further complement components [35, 36], as well as the release of reactive oxygen and nitrogen species [37, 38], altogether leading to dysfunction and loss of synapse signaling [39]. Pro-inflammatory mediators provoke a number of stress conditions which, in turn, can enhance APP production and processing to amyloid peptides (Aβ 1–42) [40–45]. Thus, chronic and self-sustaining inflammatory interactions between the complement system, activated microglia, stressed neurons, and Aβ plaques occur, which ultimately lead to neuronal cell death and cognitive decline in AD patients. Our intention was to target the pro-inflammatory complement activation product C5a in order to interfere with enhanced microglia activation and sustained neuroinflammation in AD (Fig. 8).Fig. 8

Bottom Line: Especially, complement factor C5a and its receptor have been found to be up-regulated in microglia in the immediate surroundings of cerebral amyloid plaques and blocking of C5aR resulted in a reduction of pathological markers in a model of AD.Both C5a-targeting vaccines were highly immunogenic and induced sustained antibody titers against C5a.C5a-peptide vaccines represent a safe and well-tolerated immunotherapy, which is able to induce a strong and specific immune response against the pro-inflammatory molecule C5a.

View Article: PubMed Central - PubMed

Affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. christine.landlinger@affiris.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by neuronal loss due to amyloid beta aggregations, neurofibrillary tangles, and prominent neuroinflammation. Recently, interference with neuroinflammation as a new therapeutic approach for AD treatment gained great interest. Microglia cells, one of the major contributors in neuroinflammation, are activated in response to misfolded proteins such as amyloid β and cell debris leading to a sustained release of pro-inflammatory mediators. Especially, complement factor C5a and its receptor have been found to be up-regulated in microglia in the immediate surroundings of cerebral amyloid plaques and blocking of C5aR resulted in a reduction of pathological markers in a model of AD. Here, we investigate the effect of active vaccination against the complement factor C5a to interfere with neuroinflammation and neuropathologic alterations in a mouse model of AD.

Methods: Short antigenic peptides AFF1 and AFF2, which mimic a C-terminal epitope of C5a, were selected and formulated to vaccines. These vaccines are able to induce a highly specific antibody response to the target protein C5a. Tg2576 mice, a common model of AD, were immunized with these two C5a-peptide vaccines and the induced immune response toward C5a was analyzed by ELISA and Western blot analysis. The influence on memory retention was assessed by a contextual fear conditioning test. Microglia activation and amyloid plaque deposition in the brain was visualized by immunohistochemistry.

Results: Both C5a-targeting vaccines were highly immunogenic and induced sustained antibody titers against C5a. Tg2576 mice vaccinated at early stages of the disease showed significantly improved contextual memory accompanied by the reduction of microglia activation in the hippocampus and cerebral amyloid plaque load compared to control mice. Late-stage immunization also showed a decrease in the number of activated microglia, and improved memory function, however, had no influence on the amyloid β load.

Conclusion: C5a-peptide vaccines represent a safe and well-tolerated immunotherapy, which is able to induce a strong and specific immune response against the pro-inflammatory molecule C5a. In a mouse model of AD, C5a-peptide vaccines reduce microglia activation and thus neuroinflammation, which is supposed to lead to reduced neuronal dysfunction and AD symptomatic decline.

No MeSH data available.


Related in: MedlinePlus