Different strategies for treatment and prevention of Alzheimer’s disease (AD) are currently under investigation, including passive immunization with anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of Aβ-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted Z SYM73 -albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric Z SYM73 affibody for sequestering of monomeric Aβ-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with Z SYM73 -ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric Aβ, demonstrating a therapeutic potential for prevention of AD.
Germany), a high throughput surface plasmon resonance imaging analytical biosensor. cSNK-BSA was immobilized on a sensorchip and serial samples of all mice injected. In a subsequent experiment, the Ig isotype/subclass distribution of serial samples of 20 mice were evaluated: diluted plasma were injected, followed by injections of goat anti-mouse IgA, IgM, IgG, IgG1, IgG2a, IgG2ab, IgG2c and IgG3. Results: Adjuvant-treated mice had no detectable antibodies to cSNK, whilst all cSNK-immunized mice generated high levels of anti-cSNK antibodies commencing at 4 weeks post-vaccination, age month 4. Peak antibody levels were attained at 8 weeks post-vaccination, age month 5, after which levels varied and declined slightly but remained substantially higher than levels at month 4. Ig isotype/ subclass analysis revealed that anti-cSNK antibodies are overwhelmingly of the IgG isotype and predominantly of the IgG1 subclass. Conclusions: Immunization of APP/ PS1 mice with the cSNK tripeptide induces high and sustained levels of anti-cSNK antibodies that demonstrated binding to AbO. Anti-cSNK antibodies are predominantly of the IgG1 isotype, this being indicative of a Th2 immune response.
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