Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain A beta levels

Background/Objectives: Active and passive immunization methodologies against amyloid-beta (A beta) are employed to clear and reduce cerebral A beta towards treatment of Alzheimer's disease (AD) patients. The therapeutic potential of these antibodies in AD patients is limited because of adverse inflammatory reactions and cerebral hemorrhage, which are associated with the treatment. We propose a novel approach to inhibit A beta production via antibodies against the beta-secretase cleavage site of the amyloid precursor protein (APP). Such an approach limits APP processing by beta-secretase, mainly through the enclocytic pathway, and overcomes some of the limitations of BACE inhibition. Anti-APP beta-site antibodies, tested in a cellular model expressing wild-type APP, were found to bind full-length APP, internalize into the cells and interfere with BACE activity, inhibiting both intraand extracellular A beta pepticle formation. Methods:We investigated the effect of anti-beta-site antibodies in an AD animal model regarding antibody efficacy, as well as possible adverse effects in the brain and periphery that may result from antibody treatment. Results/Conclusions: Here, we show that long-term systemic administration of anti-APP beta-site antibodies to Tg2576 transgenic mice improved mouse cognitive functions associated with a reduction in both brain inflammation and the incidence of microhemorrhage. Furthermore, antibody treatment did not induce any peripheral autoimmunity responses. In spite of the beneficial effects observed in anti body-treated mice, brain A beta levels were not altered as a result of antibody treatment. Copyright (c) 2007 S. Karger AG, Basel.