Amelioration of amyloid load by anti-Aβ single-chain antibody in Alzheimer mouse model

Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid β-peptide (Aβ) prevented or reduced Aβ deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Aβ, however, was halted due to brain inflammation, presumably induced by a toxic Aβ, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Aβ vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Aβ also induced clearance of amyloid plaques in the model mice, injection of humanized Aβ antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Aβ immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Aβ as well as amyloid plaques in the brain. The scFv inhibited Aβ amyloid fibril formation and Aβ-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Aβ deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Aβ may be useful to treat AD patients without eliciting brain inflammation.