title: Naturally occurring autoantibodies against Aβ oligomers exhibited more beneficial effects in the treatment of mouse model of Alzheimer's disease than intravenous immunoglobulin.
abstract: Alzheimer's disease (AD) is characterized by memory loss, intracellular neurofibrillary tangles, and extracellular plaque deposits composed of β-amyloid (Aβ). Previous reports showed that naturally occurring autoantibodies, such as intravenous immunoglobulin (IVIG), benefited patients with moderate-stage AD who carried an APOE-ε4 allele. However, the mechanism underlying the role of IVIG remains unclear. In this study, we identified naturally occurring autoantibodies against Aβ oligomers (NAbs-Aβo), which were purified by Aβ42 oligomer or Cibacron Blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs, respectively. Oli-NAbs and Blue-NAbs recognized Aβ42 oligomers or both Aβ40 and 42 oligomers, differently. Both antibodies inhibited Aβ42 aggregation and attenuated Aβ42-induced cytotoxicity. Compared with vehicles, Oli-NAbs, Blue-NAbs and IVIG significantly improved the memory and cognition, and reduced the soluble and oligomeric Aβ levels in APPswe/PS1dE9 transgenic mice. Further investigation showed that Blue-NAbs at increased doses effectively decreased plaque burden and insoluble Aβ levels, whereas Oli-NAbs significantly declined the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines in vivo. Therefore, high levels of these antibodies against oligomeric Aβ40 or Aβ42 were required, correspondingly, to achieve the optimal effect. NAbs-Aβo could be condensed to a high concentration by affinity chromatography and its isolation from IVIG may not interfere with the normal function of conventional IVIG as its concentration is very low. Thus, the isolated NAbs-Aβo as an extra product of plasma required low cost and the enriched NAbs-Aβo may be more feasible than IVIG for the treatment of AD.
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; School of Life Science, AnHui Agricultural University, HeFei 230036, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Xi-Xiu
authors.initials: XX
authors.lastname: Xie
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ji
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Shao-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zha
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhou
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Yu
authors.affiliation: National Institutes for Food and Drug Control, Beijing 100050, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wei
authors.affiliation: Shandong Institute of Biological Products, Taian 2710000, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Ma
authors.affiliation: Shandong Institute of Biological Products, Taian 2710000, China.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Xi
authors.affiliation: Shandong Institute of Biological Products, Taian 2710000, China. Electronic address: pgl@ctbb.com.cn.
authors.forename: Guang-Li
authors.initials: GL
authors.lastname: Pang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China. Electronic address: rtliu@home.ipe.ac.cn.
authors.forename: Rui-Tian
authors.initials: RT
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000302:isolation & purification / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007167:Immunotherapy; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology*; D055503:Protein Multimerization / Q000187:drug effects; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001323:Autoantibodies; D016207:Cytokines; D016756:Immunoglobulins, Intravenous; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D016708:Synaptophysin; C569015:Syp protein, mouse; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Antibody; Intravenous immunoglobulin; Oligomers; β-amyloid