Background/Objectives: Active and passive immunization methodologies against amyloid-β (Aβ) are employed to clear and reduce cerebral Aβtowards 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 Aβ production via antibodies against the β-secretase cleavage site of the amyloid precursor protein (APP). Such an approach limits APP processing by β-secretase, mainly through the endocytic pathway, and overcomes some of the limitations of BACE inhibition. Anti-APP β-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 intra- and extracellular Aβ peptide formation. Methods: We investigated the effect of anti-β-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 β-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 antibody-treated mice, brain Aβ levels were not altered as a result of antibody treatment.

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