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P3‐282: Investigation of low molecular weight D‐enantiomeric peptides for diagnosis and therapy of Alzheimer's disease
Author(s) -
Bartnik Dirk,
Funke Susanne A.,
Cinar Yeliz,
Brener Oleksandr,
NagelSteger Luitgard,
Wiesehan Katja,
Willbold Dieter
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.953
Subject(s) - chemistry , enantiomer , peptide , in vivo , biophysics , amyloid (mycology) , senile plaques , surface plasmon resonance , in vitro , synucleinopathies , fluorescence , biochemistry , alzheimer's disease , pathology , disease , medicine , stereochemistry , biology , nanotechnology , materials science , nanoparticle , inorganic chemistry , physics , microbiology and biotechnology , quantum mechanics , parkinson's disease , alpha synuclein
Background: Alzheimer’s vaccine ACI-24 is a liposome-based vaccine with tetra-palmitoylated amyloid beta 1-15 peptide. Recently, we demonstrated the immunogenicity and therapeutic efficacy of ACI-24 in double transgenic APPxPS1mice (Muhs et al., PNAS, 104, 9810-9815, 2007). The data presented here focus on the safety profile of ACI-24 by analyzing inflammation and hemorrhages in an Alzheimer’s disease (AD) mouse model. Methods: 27-28 month old double transgenic APPxPS-1 mice were injected intraperitoneally with 5 doses of ACI-24 or empty liposomes, at 2-week intervals. The presence of activated microglia (MHCII and CD45), astrogliosis (GFAP), and penetration into the brain of peripheral peripheral T and B-cells (CD4 and CD45) cells were analyzed by immunohistochemistry. Micro-hemorrhages were analyzed by Perl’s Iron staining and local secretion of pro-inflammatory cytokines by ELISA. Results: ACI-24 vaccine induced anti-amyloid beta antibody titers in the APPxPS1 transgenic mice with high specificity for oligomeric Amyloid beta species. These antibodies were of IgG2b and IgG3 isotypes, indicating a preferential Th2 vaccine response. The brain tissues showed no evidence of microglia activation nor astrogliosis and no increase in the levels of the pro-inflammatory cytokines IL-1beta, IL-6, TNF-alpha, or IFN-gamma. The histological staining with Perl’s Iron revealed that the number of sections per mouse containing large hemorrhages was significantly lower in mice treated with ACI-24 compared to the vehicle-treated controls. Additionally, ACI-24 immunization did not induce infiltration of peripheral monocytes (MHC-II) nor peripheral Tand B-cells (CD4 or CD45) into the brains of the treated transgenic mice. Conclusions: Our results show that immunization of old transgenic mice with ACI-24 induces oligo-specific anti-Amyloid beta antibodies and decreases the number of large micro-hemorrhages without inducing micro-hemorrhages. Furthermore, ACI-24 immunization does not cause cellular brain inflammation or enhance the release of pro-inflammatory cytokines, nor does it result in the penetration of peripheral monocytes into the brain. These results, together with the preferentially Th2 associated antibody isotype profile, indicate a low risk of encephalitis and thus demonstrates a positive safety profile for ACI-24 in a relevant AD animal model.