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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

Depletion of C5a from the circulation through C5a-peptide vaccination. The changes of C5a concentration in the plasma of Tg2576 mice before (at the age of 8 months) and after the treatment (at the age of 15 months) with AFF1- (n = 12), AFF2- (n = 13), or vehicle- (n = 11) containing vaccines were determined by sandwich ELISA. The level of C5a in the plasma obtained before the immunization start at the age of 8 months refers to 100 %. The C5a level in the plasma of untreated wt mice (n = 6) at the age of 8 months vs. 15 months is also shown. Bars represent the group means ± SEM of n animals. The one-way ANOVA test followed by a Tukey’s multiple comparison Test (parametric test) was applied to determine the p values (*p < 0.05 and **p < 0.01)
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Fig4: Depletion of C5a from the circulation through C5a-peptide vaccination. The changes of C5a concentration in the plasma of Tg2576 mice before (at the age of 8 months) and after the treatment (at the age of 15 months) with AFF1- (n = 12), AFF2- (n = 13), or vehicle- (n = 11) containing vaccines were determined by sandwich ELISA. The level of C5a in the plasma obtained before the immunization start at the age of 8 months refers to 100 %. The C5a level in the plasma of untreated wt mice (n = 6) at the age of 8 months vs. 15 months is also shown. Bars represent the group means ± SEM of n animals. The one-way ANOVA test followed by a Tukey’s multiple comparison Test (parametric test) was applied to determine the p values (*p < 0.05 and **p < 0.01)

Mentions: The plasma concentration of C5a was used as a surrogate for antibody binding efficacy to C5a of vaccine-induced antibodies. The changes of the total C5a levels in the plasma obtained before (refers to 100 %) and after the last immunization of AFF1, AFF2, and control immunized Tg2576 mice were assessed. The levels of C5a were significantly reduced to 68 and 72 % in AFF1- and AFF2-treated mice, respectively, whereas control immunized mice showed an increase of C5a up to 124 % (Fig. 4), indicating an in vivo target engagement of AFFITOPE®-induced antibodies. As an additional control, plasma from untreated wt mice was analyzed showing a constant level of C5a in the plasma of 8- vs. 15-month-old mice (Fig. 4).Fig. 4


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)

Depletion of C5a from the circulation through C5a-peptide vaccination. The changes of C5a concentration in the plasma of Tg2576 mice before (at the age of 8 months) and after the treatment (at the age of 15 months) with AFF1- (n = 12), AFF2- (n = 13), or vehicle- (n = 11) containing vaccines were determined by sandwich ELISA. The level of C5a in the plasma obtained before the immunization start at the age of 8 months refers to 100 %. The C5a level in the plasma of untreated wt mice (n = 6) at the age of 8 months vs. 15 months is also shown. Bars represent the group means ± SEM of n animals. The one-way ANOVA test followed by a Tukey’s multiple comparison Test (parametric test) was applied to determine the p values (*p < 0.05 and **p < 0.01)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: Depletion of C5a from the circulation through C5a-peptide vaccination. The changes of C5a concentration in the plasma of Tg2576 mice before (at the age of 8 months) and after the treatment (at the age of 15 months) with AFF1- (n = 12), AFF2- (n = 13), or vehicle- (n = 11) containing vaccines were determined by sandwich ELISA. The level of C5a in the plasma obtained before the immunization start at the age of 8 months refers to 100 %. The C5a level in the plasma of untreated wt mice (n = 6) at the age of 8 months vs. 15 months is also shown. Bars represent the group means ± SEM of n animals. The one-way ANOVA test followed by a Tukey’s multiple comparison Test (parametric test) was applied to determine the p values (*p < 0.05 and **p < 0.01)
Mentions: The plasma concentration of C5a was used as a surrogate for antibody binding efficacy to C5a of vaccine-induced antibodies. The changes of the total C5a levels in the plasma obtained before (refers to 100 %) and after the last immunization of AFF1, AFF2, and control immunized Tg2576 mice were assessed. The levels of C5a were significantly reduced to 68 and 72 % in AFF1- and AFF2-treated mice, respectively, whereas control immunized mice showed an increase of C5a up to 124 % (Fig. 4), indicating an in vivo target engagement of AFFITOPE®-induced antibodies. As an additional control, plasma from untreated wt mice was analyzed showing a constant level of C5a in the plasma of 8- vs. 15-month-old mice (Fig. 4).Fig. 4

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