Sukanto Sinha, departing from his abstract (122.1), described the purification and partial characterization of a novel 501 amino acid long aspartyl protease. The data were entirely consistent with the β-secretase activities reported by SmithKline Beecham (240.11) at this meeting and by Amgen in their recent Science publication (Science 1999;286:735-741). That is: 1) the protein sequences appear identical, 2) overexpression results in an increased secretion of both Aβ1-40 and A-beta1-42, 3) the activity has an acidic pH optimum and 4) it appears to be the dominant β-secretase in neuronal cells. In the Elan study β-secretase activity was assessed by cleavage of a fusion protein that contained the C-terminal 125 amino acids of APP (APP570-695) wild-type or Swedish (K595M596 to NL, APP695 numbering) sequence. The purification regime was classical biochemistry at its best and involved: detergent extraction, lectin affinity chromatography, cation exchange chromatography and inhibitor affinity chromatography and resulted in a 55,000-fold enrichment with only a single ~70 kDa gylcoprotein detected by silver staining. Interestingly, Sinha indicated that Elan already had potent non-peptidomimetic inhibitors of BACE. The independent identification of a single protein with β-secretase activity by three different pharmaceutical companies may mean that an effective therapy for Alzheimer's disease will soon be realized.-Dominic Walsh.

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