Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the cerebellum and striatum in Alzheimer's disease and Down's syndrome.

The lysosomal hydrolases, cathepsin D (Cat D) and beta-hexosaminidase A (HEX), which are normally intracellular enzymes, colocalize with beta-amyloid in a subgroup of diffuse plaques in the cerebellum and striatum of individuals with Alzheimer's disease or Down's syndrome. Using specific antisera in combination with single- and double-label immunocytochemical techniques, extracellular hydrolase was detected in 30 to 40% of the diffuse plaques in the cerebellar molecular layer and nearly all of the diffuse plaques in the striatum. In both Alzheimer's disease and Down's syndrome, about 5 to 10% of the cerebellar Purkinje cells contained abnormally increased numbers of hydrolase-positive lysosomes despite their normal appearance by conventional histologic stains. Occasional atrophic Purkinje cells identified by Nissl stain were intensely immunostained. By confocal imaging analysis, abnormal hydrolase-laden Purkinje cell dendrites were seen coursing through some hydrolase-positive plaques and were continuous with dendritic branches that terminated within deposits of extracellular hydrolase and beta-amyloid. In the striatum, intensely immunostained abnormal-appearing neurons were commonly associated with extracellular deposits of hydrolase immunoreactivity and beta-amyloid within diffuse plaques and in the less commonly seen classical plaques. In both brain regions, other hydrolase-negative beta-amyloid deposits were seen, these being associated with blood vessels. The presence of HEX immunoreactivity in neurons, but not in glia, and its abundance in plaques support earlier studies, suggesting that neurons are the principal source of plaque hydrolase. An endosomal-lysosomal system upregulation, with increased hydrolase expression and extracellular enzyme deposition in plaques, is, like beta-amyloid deposition, an early marker of metabolic dysfunction potentially related to primary etiologic events in Alzheimer's disease and Down's syndrome.