. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477. PubMed.

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  1. This is very interesting work. The identification of over 60 BACE1 substrates using an unbiased and quantitative proteomic method sheds light on the role of β-secretase in conditions where BACE1 levels are increased. Levels of BACE1 are normally very low in peripheral tissues as well as in the epithelial cell lines used in this study. Moreover, cerebral BACE1 levels decrease postnatally (Willem et al. 2006). Altogether these findings indicate that in normal conditions, β-secretase activity is low. Instead, several groups, including ours, have reported that β-secretase activity is increased in stress conditions (cerebral ischemia, traumatic brain injury, energy deprivation, hypoxia, apoptosis). Thus, this study is particularly interesting because it demonstrates that increased β-secretase activity results in alteration of normal cellular functions, e.g., the missorting of lysosomal hydrolases and increased cleavage of cell adhesion molecules, which may be detrimental for the cell. Given that BACE1 is elevated in AD brains, increased cleavage of additional substrates may contribute to AD pathology. Thus, β-secretase inhibition is expected to be beneficial in conditions associated with increased levels of BACE1.

    References:

    . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.

  2. This is an interesting approach and could hold promise in the clinic. However, the paper describes a genetic knockdown approach. The progression of a small molecule combination therapy to the clinic would be more challenging.

    Issues that would need to be addressed include assessing potential drug-drug interactions in humans. In the meantime, both tool γ-secretase and BACE inhibitors are available to test this theory in APP transgenic mice. These studies would need to be done to assess the potential of small molecule combinations and to assess any potential toxicity issues.

  3. The β-secretase (BACE1) protease is one of the enzymes that cleaves the amyloid precursor protein (APP) and leads to the production of Aβ peptides. In Alzheimer disease, elevated expression of this enzyme is thought to underlie increased Aβ production and lead to pathological effects. As such, BACE1 is an attractive therapeutic target. However, as pointed out by the authors of this paper, the normal function of BACE1 is still not well understood. Although it was known that APP is not the only target of BACE1, few targets had been identified to date. In addition, in BACE1 knockout mice, various problems have been reported, suggesting that BACE1 has important roles in the nervous system. In this paper, the Selkoe laboratory performed a quantitative proteomic analysis to identify BACE1 substrates using cell culture systems in which they overexpress the protease. They identified 68 putative substrates and validated several of these. In addition, they identified various other proteins that are not membrane bound and are likely elevated by indirect effects. The putative substrates were identified in two cell lines that express very low levels of BACE1, and the results identified many differences between cells. This study illustrates the complexities associated with targeting the expression of BACE1 as a therapeutic strategy in Alzheimer disease and provides important fundamental information. It seems that the challenges moving forward will be to identify relevant substrates in neurons that express BACE1 and to determine the relative importance of various BACE1 substrates.