Indepth Characterization

The identification and initial characterization of p-secretase triggered numerous lines of investigation that can be summarized by their major themes. Only some publications are cited as examples.

Characterization of BACE1 Several groups reported characterization of purified BACE1 protein. As an example, Haniu et al. (2000) established the disulfide bond connectivity and the glycosylation of BACE1. Other publications focused on expression studies and on the cell biology of BACE1, its processing, subcellular localization, trafficking, etc.

Crystallization of BACE1 The identification of BACE1 triggered a race to crystallize and solve the structure of its ectodomain (containing the protease activity). This task was first accomplished by Hong et al. (2000), who demonstrated that the overall structure of the enzyme is very similar to that of other known aspartic proteases but that there are differences in the active site, which is generally more open and less hydrophobic.

Identification of family members Immediately after the identification of BACE database mining led to the discovery of BACE2, an aspartic protease was discovered that has 64% similarity to BACE1 and also exhibits a C-terminal transmembrane domain (Saunders et al. 1999). It is now accepted that BACE2 is not a major secretase, but its physiological role remains unclear.

Knockout studies The finding that BACE1 knockout mice are deficient in Ap production, independently reported by three groups, was not unexpected. However, these findings provided ultimate in vivo validation that BACE1 is p-secretase and demonstrated that no compensatory mechanism for p-secretase cleavage exists in mice. (Cai et al. 2001; Luo et al. 2001; Roberds et al. 2001). The more unexpected aspect of the knockout studies was the absence of major problems as a result of p-secretase ablation. BACE knockout mice were found to be healthy and fertile and were normal in terms of gross morphology and anatomy, tissue histology, hematology and clinical chemistry (Luo etal. 2001).

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