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

Accumulation and aggregation of amyloid peptide 1-42 (A 42 ) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of A 42 versus A 40 or total A is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-A 42 mAb, an anti-A 40 mAb, and multiple A 1-16 mAbs. We established in vivo binding selectivity of the anti-A 42 and anti-A 40 mAbs using novel TgBRI-A mice. We then conducted a prevention study in which the anti-A mAbs were administered to young Tg2576 mice, which have no significant A deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting A deposits. Anti-A 42 , anti-A 40 , and anti-A 1-16 mAbs attenuated plaque deposition in the prevention study. In contrast, anti-A 42 and anti-A 40 mAbs were less effective in attenuating A 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 42 or A 40 may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting. Nonstandard abbreviations used: A, amyloid ; Ab2, anti-A1-16 mAb of IgG3 isotype; Ab3, anti-A1-16 mAb of IgG1 isotype; Ab5, anti-A1-16 mAb of IgG2b isotype; Ab9, anti-A1-16 mAb of IgG2a isotype; Ab40.1, anti-A40 mAb; Ab42.2, anti-A42 mAb; AD, Alzheimer disease; APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; FA, formic acid; FA A, A level measured by ELISA following FA extraction; FcR, Fc receptor; NSAID, nonsteroidal antiinflammatory drug; SDS A, A level measured by ELISA following SDS extraction.