Assembly and deposition of amyloid P-protein (AP) in the brain is a fundamental process of Alzheimer's disease (AD). We previously hypothesized that GM1 ganglioside-bound A beta (GA beta) is an endogenous seed for A beta assembly in brain. Recently, we have succeeded in generation of a monoclonal antibody specific to GAP. Notably, this antibody, 4396C, per se substantially inhibits A beta assembly in vitro. Here we report that the peripheral administration of Fab fragments of 4396C into transgenic mice expressing a mutant amyloid precursor protein gene, following the conjugation of the protein transduction domain of the Tat protein, markedly suppressed A beta deposition in the brain. This result further supports our previous hypothesis and also provides a new insight into develop AD therapy through targeting seed A beta in the brain, which selectively inhibits the initial step of the pathological process of AD. (c) 2005 Elsevier Inc. All rights reserved.