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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

At an early stage of disease, C5a-peptide vaccines reduce the number of activated microglia and amyloid plaque load in the brain. a Brain sections of 15-month-old Tg2576 mice immunized with either AFF1 (n = 23), AFF2 (n = 23), or control (n = 14) vaccines were stained for CD45-positive microglia cells (green). b The average number of CD45high cells in the hippocampal region of all sections. c Amyloid plaques visualized by the 3A5 mAB (green) (d). Percentage of amyloid area of the total brain sections all containing the hippocampal region was calculated by the eDefiniens Software. a, c Cell nuclei were stained with DAPI (blue) and the scale bar refers to 100 μm. b, dBars represent the group means ± SEM of n animals. The p value was determined using one-way ANOVA test followed by a Dunn’s multiple comparison Test (non-parametric test) and expressed as *p < 0.05 and **p < 0.01
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Fig6: At an early stage of disease, C5a-peptide vaccines reduce the number of activated microglia and amyloid plaque load in the brain. a Brain sections of 15-month-old Tg2576 mice immunized with either AFF1 (n = 23), AFF2 (n = 23), or control (n = 14) vaccines were stained for CD45-positive microglia cells (green). b The average number of CD45high cells in the hippocampal region of all sections. c Amyloid plaques visualized by the 3A5 mAB (green) (d). Percentage of amyloid area of the total brain sections all containing the hippocampal region was calculated by the eDefiniens Software. a, c Cell nuclei were stained with DAPI (blue) and the scale bar refers to 100 μm. b, dBars represent the group means ± SEM of n animals. The p value was determined using one-way ANOVA test followed by a Dunn’s multiple comparison Test (non-parametric test) and expressed as *p < 0.05 and **p < 0.01

Mentions: In order to investigate the impact of anti-C5a vaccination on microgliosis in the hippocampus, immunohistochemical analysis of CD45high cells in the brain of AFF1-, AFF2-, and control-treated Tg2576 mice at the age of 15 months was performed (Fig 6a). Compared to control, both AFF1- and AFF2-formulated vaccines significantly reduced the number of CD45-positive (CD45high) microglia in the hippocampus (Fig. 6b).Fig. 6


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)

At an early stage of disease, C5a-peptide vaccines reduce the number of activated microglia and amyloid plaque load in the brain. a Brain sections of 15-month-old Tg2576 mice immunized with either AFF1 (n = 23), AFF2 (n = 23), or control (n = 14) vaccines were stained for CD45-positive microglia cells (green). b The average number of CD45high cells in the hippocampal region of all sections. c Amyloid plaques visualized by the 3A5 mAB (green) (d). Percentage of amyloid area of the total brain sections all containing the hippocampal region was calculated by the eDefiniens Software. a, c Cell nuclei were stained with DAPI (blue) and the scale bar refers to 100 μm. b, dBars represent the group means ± SEM of n animals. The p value was determined using one-way ANOVA test followed by a Dunn’s multiple comparison Test (non-parametric test) and expressed as *p < 0.05 and **p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: At an early stage of disease, C5a-peptide vaccines reduce the number of activated microglia and amyloid plaque load in the brain. a Brain sections of 15-month-old Tg2576 mice immunized with either AFF1 (n = 23), AFF2 (n = 23), or control (n = 14) vaccines were stained for CD45-positive microglia cells (green). b The average number of CD45high cells in the hippocampal region of all sections. c Amyloid plaques visualized by the 3A5 mAB (green) (d). Percentage of amyloid area of the total brain sections all containing the hippocampal region was calculated by the eDefiniens Software. a, c Cell nuclei were stained with DAPI (blue) and the scale bar refers to 100 μm. b, dBars represent the group means ± SEM of n animals. The p value was determined using one-way ANOVA test followed by a Dunn’s multiple comparison Test (non-parametric test) and expressed as *p < 0.05 and **p < 0.01
Mentions: In order to investigate the impact of anti-C5a vaccination on microgliosis in the hippocampus, immunohistochemical analysis of CD45high cells in the brain of AFF1-, AFF2-, and control-treated Tg2576 mice at the age of 15 months was performed (Fig 6a). Compared to control, both AFF1- and AFF2-formulated vaccines significantly reduced the number of CD45-positive (CD45high) microglia in the hippocampus (Fig. 6b).Fig. 6

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