Although there is evidence that beta-amyloid impairs synaptic function, the relationship between beta-amyloid and synapse loss is not well understood. In this study we assessed synapse density within the hippocampus and the entorhinal cortex of Tg2576 mice at 6-18 months of age using stereological methods at both the light and electron microscope levels. Under light microscopy we failed to find overall decreases in the density of synaptophysin-positive boutons in any brain areas selected, but bouton density was significantly decreased within 200 mum of compact beta-amyloid plaques in the outer molecular layer of the dentate gyrus and Layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. Under electron microscopy, we found overall decreases in synapse density in the outer molecular layer of the dentate gyrus at both 6-9 and 15-18 months of age, and in Layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. However, we did not find overall changes in synapse density in the stratum radiatum of the CA1 subfield. Furthermore, in the two former brain areas we found a correlation between lower synapse density and greater proximity to beta-amyloid plaques. These results provide the first quantitative morphological evidence at the ultrastructure level of a spatial relationship between beta-amyloid plaques and synapse loss within the hippocampus and the entorhinal cortex of Tg2576 mice.