Cathepsin D From Alzheimer\u27s-Diseased and Normal Brains

An acid protease activity from human brain was found to cleave a fluorogenic peptide substrate encompassing the amino terminus of Alzheimer\u27s amyloid-β peptide (Aβ). The protease was isolated and determined to be cathepsin D based on chromatographic, immunological, and enzymatic data. Analysis of the cleavage sites indicated that cathepsin D hydrolyzed the methionine-aspartate bond generating the in vivo amino terminus of Aβ. These data suggested that cathepsin D could be involved in amyloidogenic processing of the amyloid precursor protein. Consequently cathepsin D from both Alzheimer\u27s-diseased and control brains was compared to determine whether there were any differences which could account for an increase in Aβ production in Alzheimer\u27s disease. No differences were detected in isoform composition or tissue content of cathepsin D as measured by 2-D IEF-SDS-PAGE. Enzymological characterization of brain cathepsin D demonstrated that it could undergo a previously undescribed pH-dependent reversible activation. However, that activation appeared identical for both AD and normal brain enzymes. These data demonstrate that concentration, isoform distribution, and several enzymological characteristics of cathepsin D are not distinguishable between AD and normal brain. The pH dependence of cathepsin D activity suggests, however, that its intracellular localization may be important in considering the potential role of cathepsin D in Alzheimer\u27s disease