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

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