Characterization of Cysteine Cathepsin Expression in the Central Nervous System of Aged Wild-Type and Cathepsin-Deficient Mice

The association of cathepsin proteases in neurobiology is increasingly recognized. Our previous studies indicated that cathepsin-K-deficient (Ctsk-/-) mice have learning and memory impairments. Alterations in cathepsin expression are known to result in compensatory changes in levels of related cathepsins. To gain insight into the therapeutic usefulness of cathepsin inhibitors in aging individuals with osteoporosis or neurodegenerative diseases, we studied for variations in cathepsin expression and activity in aged (18-20 months) versus young (5-7 months) wild-type (WT) and cathepsin-deficient mice brains. There were age-dependent increases in cathepsin B, D, and L and cystatin C protein levels in various brain regions, mainly of WT and Ctsk-/- mice. This corresponded with changes in activity levels of cathepsins B and L, but not cathepsin D. In contrast, very little age-dependent variation was observed in cathepsin-B-and cathepsin-L-deficient mouse brain, especially at the protein level. The observed alterations in cathepsin protein amounts and activity are likely contributing to changes in important aging-related processes such as autophagy. In addition, the results provide insight into the potential impact of cathepsin inhibitor therapy in aged individuals, as well as in long-term use of cathepsin inhibitor therapy.