We have previously demonstrated that chronic treatment with 3D6 significantly increases the incidence of microhemorrhage (Racke et al., 2005). In this study, we again observed

a dramatic increase in microhemorrhage with 3D6 treatment (p < 0.001) (Figure 4C). Significantly, the 3D6-dependent exacerbation of microhemorrhage occurred even in the absence of plaque lowering. In contrast, treatment with either mE8-IgG1 or mE8-IgG2a did not significantly increase microhemorrhage, even though these Aβp3-x antibodies were able to reduce LY294002 deposited Aβ. These results demonstrate that treatment with the Aβp3-x antibodies in aged PDAPP mice with maximal plaque loads was able to reduce existing deposited Aβ without CAA-related microhemorrhage liability. To investigate whether the Aβp3-x antibody mE8-IgG2a would be efficacious at preventing plaque deposition, we performed a study in 5.5-month-old PDAPP mice, an age before ABT-888 mouse the initiation of Aβ deposition, with the following antibodies: negative control antibody (IgG2a), 3D6, and mE8-IgG2a. A time zero group and an additional parallel untreated group of transgenic mice were incorporated in

the study to determine the time course of deposition. As expected, the time zero animals (5.5 months of age) lacked deposited Aβ42 (Figure 5C). In hippocampus, a dramatic accumulation of deposited Aβ42 occurred throughout the study period (∼45-fold) with the majority depositing during the latter 2 months of the study (∼80% between months 10.5 and 12.5). Consistent with previous reports for similar N-terminal antibodies, treatment

with 3D6 resulted in a significant ∼68% decrease of hippocampal Aβ42 (p < 0.001) as compared to the control IgG, although levels were higher than the untreated animals sacrificed at 10.5 months of age. The mE8-IgG2a treatment resulted in a nonsignificant ∼30% decrease in Aβ42 as compared to the control until IgG-treated mice. Similar results were observed in the cortical extracts from these mice (Figure 5D). These results demonstrate that while the phagocytic mechanism of the Aβp3-x antibody is able to clear deposited Aβ, it is less effective at preventing Aβ42 deposition in young PDAPP mice. In contrast, the N-terminal antibody 3D6, which binds soluble and insoluble Aβ, reveals an opposite pattern of efficacy (no clearance of established plaque and strong prevention of deposition), thereby suggesting that the major mechanism of action for these two antibodies is different. We sought to determine the mechanism of action responsible for the differential effects on plaque lowering observed for the Aβp3-x and 3D6 antibodies by performing in vivo target engagement studies.