An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect

Background: Senile plaques consisting of amyloid-beta (A beta) are the major pathological hallmark of Alzheimer's disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain A beta deposits, increased levels of soluble A beta and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of A beta deposition might facilitate the formation of more toxic A beta oligomers and enhance neurotoxicity. Methods: The capacity of antibodies against different epitopes of A beta to disaggregate preformed A beta fibrils was investigated. The co-incubation of antibodies and A beta fibrils was then tested for neurotoxicity both in vitro and in vivo. Results: After the incubation of preformed A beta fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of A beta (8G7). The co-incubates of preformed A beta fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7. Conclusions: Our results indicate that the antibody targeting the N-terminus of A beta promoted the transformation of A beta from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of A beta deposits by antibodies against the Nterminus of A beta.