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While major aspects of p-secretase biology have been solved, there are several very active areas of investigation, both in academia and in the pharmaceutical industry. Key research fields are:

Analysis of the role of BACE1 in AD pathogenesis No mutations in BACE1 or its promoter that would cause familial Alzheimer's disease have been reported. But there are several studies reporting increased levels of BACE1 protein in AD brains (for example Holsinger et al. 2002). Future work will show, whether BACE1 upregulation is involved in the pathogenesis of sporadic AD or if BACE1 upregulation is just one of numerous changes observed in post-mortem AD brains.

Regulation of p-secretase activity The regulation of p-secretase activity is not well understood. Several academic groups are pursuing studies to better characterize potential regulators of p-secretase activity in vitro and in vivo. Whether such studies will identify additional targets to modulate the activity of p-secretase in Alzheimer's disease remains to be seen.

Identification of p-secretase substrates other than APP The normal physiological role of BACE1 remains unclear. Our demonstration that wild type APP is not a very good substrate for BACE1 (Vassar et al. 1999) is consistent with the idea that BACE1 may have a physiological function other than Ap generation. The identification of additional BACE1 substrates may provide guidance about what potential side effects of BACE1 inhibition one may have to consider.

Identification of drug-like p-secretase inhibitors Work on p-secretase inhibitors is currently the most active area of p-secretase research. A number of peer-reviewed publications and even more published patent applications have described molecules with improved properties relative to the large peptidomimetics of the 1990s (for a recent review, see Thompson et al. 2005). Ultimately, these molecules may help to clinically test the amyloid hypothesis and in the process contribute to a better understanding of the physiological role of p-secretase. Our discovery of BACE1 as the major p-secretase enzyme has not provided additional support for the amyloid hypothesis, because no BACE1 (upregulating) mutations that cause AD have been identified yet. Rather, the identification of p-secretase has provided one of the best targets to clinically test the hypothesis, and numerous efforts in inhibitor development are ongoing, which may well be the most important consequence of our findings.

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Allen D. Roses

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