Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid beta-peptide (A beta) prevented or reduced A beta deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic A beta, however, was halted due to brain inflammation, presumably induced by a toxic A beta, 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 A beta vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against A beta also induced clearance of amyloid plaques in the model mice, injection of humanized A beta antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for A beta immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric A beta as well as amyloid plaques in the brain. The scFv inhibited A beta amyloid fibril formation and A beta-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD Jg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced A beta deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against A beta may be useful to treat AD patients without eliciting brain inflammation. (c) 2006 Elsevier Inc. All rights reserved.