CATHEPSIN-D FROM ALZHEIMERS DISEASED AND NORMAL BRAINS

An acid protease activity from human brain was found to cleave a fluor ogenic peptide substrate encompassing the amino terminus of Alzheimer' s amyloid-P peptide (AP). 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 hydrol yzed the methionine-aspartate bond generating the in vivo amino termin us of Ap. These data suggested that cathepsin D could be involved in a myloidogenic processing of the amyloid precursor protein. Consequently , cathepsin D from both Alzheimer's-diseased and control brains was co mpared to determine whether there were any differences which could acc ount for an increase in A beta production in Alzheimer's disease. No d ifferences were detected in isoform composition or tissue content of c athepsin D as measured by 2-D IEF-SDS-PAGE. Enzymological characteriza tion of brain cathepsin D demonstrated that it could undergo a previou sly undescribed pH-dependent reversible activation. However, that acti vation 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 importa nt in considering the potential role of cathepsin D in Alzheimer's dis ease. (C) 1995 Academic Press, Inc.