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


CONCLUSIONS
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.
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. christine.landlinger@affiris.com.
Christine
C
Landlinger
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. lisa.oberleitner@affiris.com.
Lisa
L
Oberleitner
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. petra.gruber@affiris.com.
Petra
P
Gruber
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. bnoiges@gmx.at.
Birgit
B
Noiges
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. kristyna.yatsyk@affiris.com.
Kristyna
K
Yatsyk
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. radmila.santic@affiris.com.
Radmila
R
Santic
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. markus.mandler@affiris.com.
Markus
M
Mandler
AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria. guenther.staffler@affiris.com.
Guenther
G
Staffler
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D005239:Fear; D005260:Female; D007115:Immunization Schedule; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008568:Memory; D051379:Mice; D017628:Microglia / Q000187:drug effects; D058225:Plaque, Amyloid / Q000473:pathology; D011597:Psychomotor Performance; D014611:Vaccination; D022223:Vaccines, Subunit / Q000627:therapeutic use
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D022223:Vaccines, Subunit; D015936:Complement C5a