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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

Vaccination at a progressed stage of disease improves memory function and reduces microgliosis but had no effect on the amyloid plaque load in the brain. a Tg2576 mice which were immunized with AFF1- (n = 9) and control (n = 9) vaccines at the age of 11 months, as well as wt littermates (n = 24) were exposed to a contextual fear conditioning test. b Average number of CD45high cells in the hippocampal region analyzed by immunohistochemistry. c The percentage of amyloid plaque area of the total brain sections. The bars represent the group means ± SEM of n animals. The unpaired two-tailed Student’s t-test was used for statistical analysis, whereas in Fig. 7a, a Mann Whitney correction for non-parametric data was performed. A p value of ≤0.05 was considered to be statistically significant
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Fig7: Vaccination at a progressed stage of disease improves memory function and reduces microgliosis but had no effect on the amyloid plaque load in the brain. a Tg2576 mice which were immunized with AFF1- (n = 9) and control (n = 9) vaccines at the age of 11 months, as well as wt littermates (n = 24) were exposed to a contextual fear conditioning test. b Average number of CD45high cells in the hippocampal region analyzed by immunohistochemistry. c The percentage of amyloid plaque area of the total brain sections. The bars represent the group means ± SEM of n animals. The unpaired two-tailed Student’s t-test was used for statistical analysis, whereas in Fig. 7a, a Mann Whitney correction for non-parametric data was performed. A p value of ≤0.05 was considered to be statistically significant

Mentions: In order to determine if the beneficial effects of our anti-C5a vaccines which were observed upon early stage treatment could also be seen in a more progressed stage of Alzheimer-like disease, AFFITOPE® immunization was started at the age of 11 months, where memory deficits and cerebral amyloid depositions are already clearly pronounced. Mice were immunized with AFF1-containing vaccines 4 times in a biweekly interval followed by the final immunization 1 month later. A contextual fear conditioning test was performed at the age of 15 months in order to assess the influence of the anti-C5a vaccination on memory impairment. Compared to the control vaccine, AFF1-vaccinated mice showed a tendency of better contextual learning and memory skills indicated by 18 % vs. 7 % time freezing (Fig. 7a,p = 0.182). Untreated wt littermates showed 51 % time freezing similar to the result obtained in Fig. 5. Again, wt littermates treated with AFF1 vaccine have not been included in this study. However, an independently performed control experiment showed that the memory retention of control and AFF1-immunized wt mice was similar (see Fig. 2a).Fig. 7


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)

Vaccination at a progressed stage of disease improves memory function and reduces microgliosis but had no effect on the amyloid plaque load in the brain. a Tg2576 mice which were immunized with AFF1- (n = 9) and control (n = 9) vaccines at the age of 11 months, as well as wt littermates (n = 24) were exposed to a contextual fear conditioning test. b Average number of CD45high cells in the hippocampal region analyzed by immunohistochemistry. c The percentage of amyloid plaque area of the total brain sections. The bars represent the group means ± SEM of n animals. The unpaired two-tailed Student’s t-test was used for statistical analysis, whereas in Fig. 7a, a Mann Whitney correction for non-parametric data was performed. A p value of ≤0.05 was considered to be statistically significant
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Vaccination at a progressed stage of disease improves memory function and reduces microgliosis but had no effect on the amyloid plaque load in the brain. a Tg2576 mice which were immunized with AFF1- (n = 9) and control (n = 9) vaccines at the age of 11 months, as well as wt littermates (n = 24) were exposed to a contextual fear conditioning test. b Average number of CD45high cells in the hippocampal region analyzed by immunohistochemistry. c The percentage of amyloid plaque area of the total brain sections. The bars represent the group means ± SEM of n animals. The unpaired two-tailed Student’s t-test was used for statistical analysis, whereas in Fig. 7a, a Mann Whitney correction for non-parametric data was performed. A p value of ≤0.05 was considered to be statistically significant
Mentions: In order to determine if the beneficial effects of our anti-C5a vaccines which were observed upon early stage treatment could also be seen in a more progressed stage of Alzheimer-like disease, AFFITOPE® immunization was started at the age of 11 months, where memory deficits and cerebral amyloid depositions are already clearly pronounced. Mice were immunized with AFF1-containing vaccines 4 times in a biweekly interval followed by the final immunization 1 month later. A contextual fear conditioning test was performed at the age of 15 months in order to assess the influence of the anti-C5a vaccination on memory impairment. Compared to the control vaccine, AFF1-vaccinated mice showed a tendency of better contextual learning and memory skills indicated by 18 % vs. 7 % time freezing (Fig. 7a,p = 0.182). Untreated wt littermates showed 51 % time freezing similar to the result obtained in Fig. 5. Again, wt littermates treated with AFF1 vaccine have not been included in this study. However, an independently performed control experiment showed that the memory retention of control and AFF1-immunized wt mice was similar (see Fig. 2a).Fig. 7

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