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Article
Deglycosylated anti-amyloid beta antibodies induce amyloid beta sequestration with reduced microglial phagocytosis and cytokine release
European Journal of Neuroscience
  • Kazuyuki Takata, Kyoto Pharmaceutical University
  • Chiho Hirata-Fukae, Georgetown University Medical Center
  • Amanda G. Becker, Georgetown University Medical Center
  • Saori Chishiro, Kyoto Pharmaceutical University
  • Audrey J. Gray, Georgetown University Medical Center
  • Kouhei Nishitomi, Discovery Research Laboratories
  • Andreas H. Franz, University of the Pacific
  • Gaku Sakaguchi, Discovery Research Laboratories
  • Akira Kato, Discovery Research Laboratories
  • Mark P. Mattson, National Institute on Ageing
  • Frank M. LaFerla, University of California, Irvine
  • Paul S. Aisen, Georgetown University Medical Center
  • Yoshihisa Kitamura, Kyoto Pharmaceutical University
  • Yasuji Matsuoka, Georgetown University Medical Center
Document Type
Article
Department
Chemistry
DOI
10.1111/j.1460-9568.2007.05852.x
Publication Date
11-1-2007
Disciplines
Abstract
Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.
Citation Information
Kazuyuki Takata, Chiho Hirata-Fukae, Amanda G. Becker, Saori Chishiro, et al.. "Deglycosylated anti-amyloid beta antibodies induce amyloid beta sequestration with reduced microglial phagocytosis and cytokine release" European Journal of Neuroscience Vol. 26 Iss. 9 (2007) p. 2458 - 2468 ISSN: 0953-816X
Available at: http://works.bepress.com/andreas-franz/106/