An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-beta (A beta) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble V aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, A beta protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from A beta protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), A beta protofibril levels were lowered while measures of insoluble A beta were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and A beta protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that A beta protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble V deposits, similar to those of Alzheimer's disease brain. (C) 2009 Elsevier Inc. All rights reserved.