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Vivian Hook, Thomas Toneff, Matthew Bogyo, Doron Greenbaum, Katalin F. Medzihradszky, John Neveu, William Lane, Gregory Hook, Terry Reisine

Inhibition of cathepsin B reduces ?-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate ?-secretase of Alzheimer's disease

Keywords: ?-amyloid, ?-secretase, cathepsin B, cysteine protease, regulated secretory pathway

The regulated secretory pathway of neurons is the major source of extracellular A? that accumulates in Alzheimer's disease (AD). Extracellular A? secreted from that pathway is generated by ?-secretase processing of amyloid precursor protein (APP). Previously, cysteine protease activity was demonstrated as the major ?-secretase activity in regulated secretory vesicles of neuronal chromaffin cells. In this study, the representative cysteine protease activity in these secretory vesicles was purified and identified as cathepsin B by peptide sequencing. Immunoelectron microscopy demonstrated colocalization of cathepsin B with A? in these vesicles. The selective cathepsin B inhibitor, CA074, blocked the conversion of endogenous APP to A? in isolated regulated secretory vesicles. In chromaffin cells, CA074Me (a cell permeable form of CA074) reduced by about 50% the extracellular A? released by the regulated secretory pathway, but CA074Me had no effect on A? released by the constitutive pathway. Furthermore, CA074Me inhibited processing of APP into the COOH-terminal ?-secretase-like cleavage product. These results provide evidence for cathepsin B as a candidate ?-secretase in regulated secretory vesicles of neuronal chromaffin cells. These findings implicate cathepsin B as ?-secretase in the regulated secretory pathway of brain neurons, suggesting that inhibitors of cathepsin B may be considered as therapeutic agents to reduce A? in AD.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 386, 09/2005
Pages: 931 - 940

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