Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta.

Abstract

Amyloid beta (Abeta) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-Abeta antibodies act against amyloid deposition and cognitive deficits remain elusive. To test the "peripheral sink" theory, which postulates that the effects of anti-Abeta antibodies in the systemic circulation are to promote the Abeta efflux from brain to blood, we studied the clearance of (125)I-Abeta(1-40) microinjected into mouse brains after intraperitoneal administration of an anti-Abeta monoclonal antibody 266. (125)I-Abeta(1-40) was rapidly eliminated from brains with a half-life of approximately 30 min in control mice, whereas 266 significantly retarded the elimination of Abeta, presumably due to formation of Abeta-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer Abeta species in an antibody-bound form, without affecting that of total Abeta. We propose a novel mechanism of Abeta immunotherapy by the class of anti-Abeta antibodies that preferentially bind soluble Abeta, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of Abeta, thereby preventing the accumulation of multimeric toxic Abeta species in brains.

• Authors: Kaoru Yamada, Chiori Yabuki, Peter Seubert, Dale Schenk, Yukiko Hori, Sumio Ohtsuki, Tetsuya Terasaki, Tadafumi Hashimoto, Takeshi Iwatsubo
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 36 Pg. 11393-8 (Sep 09 2009) ISSN: 1529-2401 [Electronic] United States
• PMID: 19741145 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Antibodies, Monoclonal

Topics

• Alzheimer Disease (immunology, metabolism, therapy)
• Amyloid beta-Peptides (administration & dosage, immunology, metabolism)
• Animals
• Antibodies, Monoclonal (administration & dosage, metabolism, therapeutic use)
• Antibody Affinity
• Brain (immunology, metabolism)
• Humans
• Immunotherapy, Active (methods)
• Injections, Intraventricular
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microinjections
• Solubility