Aβ Immunotherapy: Intracerebral Sequestration of Aβ by an Anti-Aβ Monoclonal Antibody 266 with High Affinity to Soluble Aβ

• DOI: 10.1523/jneurosci.2021-09.2009
• Publication Date: 2009-09-09T18:10:07Z
• Authors: Kaoru Yamada; Chiori Yabuki; Peter Seubert; Dale Schenk; Yukiko Hori; Sumio Ohtsuki; Tetsuya Terasaki; Tadafumi Hashimoto; Takeshi Iwatsubo
• Keywords: Male; 0301 basic medicine; Amyloid beta-Peptides; Microinjections; Antibody Affinity; Antibodies, Monoclonal; Brain; Immunotherapy, Active; Mice, Transgenic; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Solubility; Alzheimer Disease; Animals; Humans; Injections, Intraventricular

Amyloid β (Aβ) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-Aβ antibodies act against amyloid deposition and cognitive deficits remain elusive. To test the “peripheral sink” theory, which postulates that the effects of anti-Aβ antibodies in the systemic circulation are to promote the Aβ efflux from brain to blood, we studied the clearance of125I-Aβ1-40microinjected into mouse brains after intraperitoneal administration of an anti-Aβ monoclonal antibody 266.125I-Aβ1-40was rapidly eliminated from brains with a half-life of ∼30 min in control mice, whereas 266 significantly retarded the elimination of Aβ, presumably due to formation of Aβ-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer Aβ species in an antibody-bound form, without affecting that of total Aβ. We propose a novel mechanism of Aβ immunotherapy by the class of anti-Aβ antibodies that preferentially bind soluble Aβ, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of Aβ, thereby preventing the accumulation of multimeric toxic Aβ species in brains.