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The Journal of Neuroscience, September 9, 2009, 29(36):11393-11398; doi:10.1523/JNEUROSCI.2021-09.2009

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

Kaoru Yamada,¹ Chiori Yabuki,¹ Peter Seubert,³ Dale Schenk,³ Yukiko Hori,¹ Sumio Ohtsuki,⁴ Tetsuya Terasaki,⁴ Tadafumi Hashimoto,^1,2 and Takeshi Iwatsubo^1,2

¹Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, and ²Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan, ³Elan Pharmaceuticals, Inc., South San Francisco, California 94080, and ⁴Department of Molecular Biopharmacy and Genetics, Tohoku University, Sendai 980-8575, Japan

Correspondence should be addressed to Takeshi Iwatsubo, Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyoku, Tokyo 113-0033, Japan. Email: iwatsubo{at}m.u-tokyo.ac.jp

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 of ¹²⁵I-Aβ_1-40 microinjected into mouse brains after intraperitoneal administration of an anti-Aβ monoclonal antibody 266. ¹²⁵I-Aβ_1-40 was 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.

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Received April 29, 2009; revised Aug. 3, 2009; accepted Aug. 6, 2009.

Correspondence should be addressed to Takeshi Iwatsubo, Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyoku, Tokyo 113-0033, Japan. Email: iwatsubo{at}m.u-tokyo.ac.jp

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