科研之友
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摘要
Senile plaques consisting of Amyloid-beta (4) peptides, in particular A beta(1-42), are the hallmark of Alzheimer's disease (AD) and have been the primary therapeutic targets. Passive immunotherapy with monoclonal antibodies (mAbs) has shown initial success in mouse models of AD. However, the existing A beta-directed mAbs mostly were tested on animal models or patients with advanced disease. The effects and mechanisms of mAbs on animals or human trial participants in the prodromal phase of AD are not fully clarified. In the current study, a novel mAb (3F5) directed against the 1-11 amino acids of A beta(1-42) was generated by immunizing mice with an emulsion of full length human A beta(1-42). The mAb (3F5) showed the ability to disrupt A beta(1-42) aggregation and prevent A beta-mediated neurotoxicity in vitro. In a mouse model of AD, administration with 3F5 for 3 months in 6 months-old mice demonstrated that the mAb specifically bound with A beta(1-42) to promote the depolymerization of A beta fibrils, facilitated endocytosis of A beta(1-42) by microglia, and attenuated the death and apoptosis of neuronal cells, accompanied by neurite outgrowth. APP/PS1 double-transgenic mice treated with 3F5 mAb showed reduced memory loss, cognitive decline, and decreased levels of amyloid deposits in the brain. A beta(1-42) levels in cerebral tissues were also significantly reduced, whereas serum A beta(1-42) was markedly increased. Interestingly, the concentration of 3F5 in peripheral circulation is much higher than that in the brain. These results indicate that 3F5 is able to cross the blood-brain barrier (BBB) to bind A beta and initiates the phagocytosis of antibody/A beta complexes by microglia in the amyloid depositing mice. 3F5 also promotes 4 efflux from the brain. As a consequence, the antibody reduces plaques in the AD mouse brain, in association with reduction in the pathology of AD.
- 出版日期2017-6-29
- 单位中国科学院大学; 中国人民解放军陆军军医大学; 中国科学院上海生命科学研究院
