Molecular dating of senile plaques in the drains of individuals with Down syndrome and in aged dogs

beta-Amyloid (A beta) is a constituent of senile plaques found with increas ing age in individuals with Down syndrome (DS) and in the canine model of a ging. Sections of DS and dog brain were immunostained using an affinity-pur ified polyclonal antibody for a posttranslationally modified A beta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristi cs of d7C16 A beta in DS and dog brain indicate that it is present in all p laque subtypes, including the thioflavin-S-negative diffuse plaques that de velop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In a ddition, d7C16-positive plaques were initially found in clusters in the sup erficial layers of the frontal and entorhinal cortex but, with advancing ag e, increasing numbers appeared in deeper layers, suggesting a progression o f A beta deposition from superficial to deeper cortical layers. Ultrastruct ural studies in DS brain were confirmed using perfused dog brain and provid ed consistent results; thioflavin-S-negative diffuse plaques consist of fib rillar A beta and racemized A beta is associated with thicker and more high ly interwoven fibrils than non-racemized A beta. The use of antibodies to m odified forms of the A beta protein should provide insight into the progres sion of plaque pathology in DS and Alzheimer's disease brain. (C) 2000 Acad emic Press.