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

Journal of Neuroinflammation

Yan-Jiang Wang¹  Juan Deng¹  Hua-Dong Zhou¹  Xiu-Qing Yao¹  Fan Zeng¹  Shu-Sheng Jiao¹  Tao Zhang¹  Ye-Ran Wang¹  Chun-Rong Liang¹  Xian-Le Bu¹  Yu-Hui Liu¹ 

[1] Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital and Research Institute of Surgery, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China

关键词: Dust-raising effect;    Fibril;    Oligomer;    N-terminal antibody;    Amyloid-beta;    Alzheimer;   

Others  :  1227074
DOI  :  10.1186/s12974-015-0379-4

 received in 2015-05-05, accepted in 2015-08-17,  发布年份 2015

【 摘 要 】

Background

Senile plaques consisting of amyloid-beta (Aβ) are the major pathological hallmark of Alzheimer’s disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aβ deposits, increased levels of soluble Aβ and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aβ deposition might facilitate the formation of more toxic Aβ oligomers and enhance neurotoxicity.

Methods

The capacity of antibodies against different epitopes of Aβ to disaggregate preformed Aβ fibrils was investigated. The co-incubation of antibodies and Aβ fibrils was then tested for neurotoxicity both in vitro and in vivo.

Results

After the incubation of preformed Aβ 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 Aβ (8G7). The co-incubates of preformed Aβ 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 Aβ promoted the transformation of Aβ from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aβ deposits by antibodies against the Nterminus of Aβ.

【 授权许可】

   
2015 Liu et al.

【 图 表 】

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