title: An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.
abstract: 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.
authors: 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. liuyuhui07-8909@163.com.
authors: Yu-Hui
authors: YH
authors: Liu
authors: 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. buxianle@sina.cn.
authors: Xian-Le
authors: XL
authors: Bu
authors: 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. liangcr2011@163.com.
authors: Chun-Rong
authors: CR
authors: Liang
authors: 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. sophietmmu@gmail.com.
authors: Ye-Ran
authors: YR
authors: Wang
authors: 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. ztchongqing@163.com.
authors: Tao
authors: T
authors: Zhang
authors: 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. xiaojiao5678@sina.com.
authors: Shu-Sheng
authors: SS
authors: Jiao
authors: 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. zengfan326@163.com.
authors: Fan
authors: F
authors: Zeng
authors: 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. dryaoxq@163.com.
authors: Xiu-Qing
authors: XQ
authors: Yao
authors: 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. zhouhuad@163.cm.
authors: Hua-Dong
authors: HD
authors: Zhou
authors: 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. dj941@sina.com.
authors: Juan
authors: J
authors: Deng
authors: 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. yanjiang_wang@tmmu.edu.cn.
authors: Yan-Jiang
authors: YJ
authors: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D016501:Neurites / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053148:Caspase 3; D010751:Phosphopyruvate Hydratase