Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional β-secretase candidate(s)
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Israel Schechter
Abstract
Many studies suggest that BACE 1 is the genuine β-secretase; however, this is not undisputed. The wild-type (WT) β-site of the amyloid precursor protein (APP) present in the worldwide population is cleaved very slowly (kcat/Km: approx. 50 m-1 s-1), while proteases acting on relevant substrates are much more efficient (kcat/Km: 104–106 m-1 s-1). Knock-out of BACE 1 in mouse markedly reduces Aβ formation. Nevertheless, studies in other systems show that knock-out experiments in rodents and corresponding genetic defects in human may reveal different phenotypes. Considering these issues, we searched for other β-secretase candidate(s), identified cathepsin D, and evaluated properties of cathepsin D related to BACE 1 that were not examined previously. The kinetic constants (kcat, Km, kcat/Km) for cleaving peptides with β-sites of the WT or the mutated Swedish families (SW) APP by human BACE 1 and cathepsin D were determined and found to be similar. Western blots reveal that in human brain cathepsin D is approximately 280-fold more abundant than BACE 1. Furthermore, pepstatin A strongly inhibits the cleavage of SW and WT peptides by both brain extracts and cathepsin D, but not by BACE 1. These findings indicate that β-secretase activity observed in brain extracts is mainly due to cathepsin D. Nevertheless, as both BACE 1 and cathepsin D show poor activity towards the WT β-site sequence, it is necessary to continue the search for additional β-secretase candidate(s).
©2008 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Highlight: Oxidative Stress and Senescence
- Regulation of proteasome-mediated protein degradation during oxidative stress and aging
- Cellular responses to reactive oxygen species-induced DNA damage and aging
- Sirt1 protects the heart from aging and stress
- Klotho as a regulator of oxidative stress and senescence
- Posttranscriptional gene regulation by RNA-binding proteins during oxidative stress: implications for cellular senescence
- Potential biomarkers of ageing
- Increased molecular damage and heterogeneity as the basis of aging
- Modulation of longevity-associated genes by estrogens or phytoestrogens
- FoxO transcription factors in oxidative stress response and ageing – a new fork on the way to longevity?
- Studies on the expression of 6S RNA from E. coli: involvement of regulators important for stress and growth adaptation
- New biological activity against phospholipase A2 by Turmerin, a protein from Curcuma longa L.
- Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs
- Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional β-secretase candidate(s)
