Molecular Dating of Senile Plaques in the Brains of Individuals with Down Syndrome and in Aged Dogs

Abstract

β-Amyloid (Aβ) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Aβ with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Aβ in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Aβ deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Aβ and racemized Aβ is associated with thicker and more highly interwoven fibrils than nonracemized Aβ. The use of antibodies to modified forms of the Aβ protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain.