Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta.
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.
Yamada
Kaoru
K
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Yabuki
Chiori
C
Seubert
Peter
P
Schenk
Dale
D
Hori
Yukiko
Y
Ohtsuki
Sumio
S
Terasaki
Tetsuya
T
Hashimoto
Tadafumi
T
Iwatsubo
Takeshi
T
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000915:Antibody Affinity; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008845:Microinjections; D012995:Solubility
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal