Anti-A beta(42)- and anti-A beta(40)-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model

Accumulation and aggregation of amyloid beta peptide 1-42 (A beta(42)) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of A beta(42) versus A beta(40) or total A beta is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-A beta(42) mAb, an anti-A beta(40) MAb, and multiple A beta(1-16) mAbs. We established in vivo binding selectivity of the anti-A beta(42) and anti-A beta(40) mAbs using novel TgBRI-A beta mice. We then conducted a prevention study in which the anti-A beta mAbs were administered to young Tg2576 mice, which have no significant A beta deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting A beta deposits. Anti-A beta(42), anti-A beta(40), and anti-A beta(1-16) mAbs attenuated plaque deposition in the prevention study. In contrast, anti-A beta(42) and anti-A beta(40) mAbs were less effective in attenuating A beta deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of A beta(42) or A beta(40) may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.