Transgenic expression of beta 1 antibody in brain neurons impairs age-dependent amyloid deposition in APP23 mice

Heterologous expression of the functional amyloid beta (A beta) antibody beta 1 in the central nervous system was engineered to maximize antibody exposure in the brain and assess the effects on A beta production and accumulation in these conditions. A single open reading frame encoding the heavy and light chains of beta 1 linked by the mouth and foot virus peptide 2A was expressed in brain neurons of transgenic mice. Two of the resulting BIN66 transgenic lines were crossed with APP23 mice, which develop severe central amyloidosis. Brain concentrations at steady-state 5 times greater than those found after peripheral beta 1 administration were obtained. Similar brain and plasma beta 1 concentrations indicated robust antibody efflux from the brain. In preplaque mice, beta 1 formed a complex with A beta that caused a modest A beta increase in brain and plasma. At 11 months of age, beta 1 expression reduced amyloid by 97% compared with age-matched APP23 mice. Interference of beta 1 with beta-secretase cleavage of amyloid precursor protein was relatively small. Our data suggest that severely impaired amyloid formation was primarily mediated by a complex of beta 1 with soluble A beta, which might have prevented A beta aggregation or favored transport out of the brain. (C) 2013 Elsevier Inc. All rights reserved