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

Abstract

BackgroundAlzheimer’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.MethodsShort 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.ResultsBoth 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.ConclusionC5a-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.

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

“…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]. AFF1 treated mice did not only show a reduced number of activated microglia in the hippocampal region, but also improved contextual learning and memory skills [37].…”

“…The proprietary AFFITOME ® technology [39] was used to develop short immunogenic peptides (AFFITOPE ® s), which mimic either the C-terminal epitope of murine C5a [37] or the N-terminal epitope of human Aβ [13]. Vaccines were prepared as described previously [37].…”

“…Induced antibody titers against the antigenic peptide moiety of AFF1, AD02, and AFF1/AD02 combinatorial vaccine were determined by ELISA as described previously [37].…”

“…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]. AFF1 treated mice did not only show a reduced number of activated microglia in the hippocampal region, but also improved contextual learning and memory skills [37]. Moreover, cerebral amyloid plaque load was diminished when vaccinated at an early stage of the disease [37].…”

“…AFF1 treated mice did not only show a reduced number of activated microglia in the hippocampal region, but also improved contextual learning and memory skills [37]. Moreover, cerebral amyloid plaque load was diminished when vaccinated at an early stage of the disease [37].…”