According to a report in tomorrow's Science, researchers have uncovered a strong candidate for β-secretase, the mystery enzyme that cleaves APP and allows Aβ to be formed in subsequent cleavages. Martin Cintron, Robert Vassar, Brian Bennett and colleagues at Amgen, Inc., report that a novel transmembrane aspartic protease termed BACE (for β-site APP-cleaving enzyme) has all the known characteristics of β-secretase.
Citron and his colleagues used an expression cloning strategy to find genes that modulate APP. Their search turned up a gene coding for a protein with a number of features associated with type I transmembrane proteins, and with its active site in the lumen, which is where β-secretase cleaves APP. They report that overexpression of this protein led to an overproduction of β-secretase products, cleaved without fail at known β-secretase sites, from both wildtype and Swedish-mutation APP. A number of other experiments also supported BACE as being β-secretase. For example, cellular and intracellular expression patterns parallel what is known about β-secretase.
Is BACE the real thing, or another hopeful candidate that will disappoint? Quoted in a News article in the same issue, Sam Sisodia of the University of Chicago said that evidence for BACE "is incontrovertible. I was floored by the data." The obvious next steps are to find inhibitors of BACE that could, in the most optimistic view, prevent or reverse Aβ deposition in Alzheimer's. At the very least, they will help answer the question of whether Aβ is the agent of neuronal destruction.—Hakon Heimer
Comment:-Posted 12 November 1999
Two groups announced today in Science that BACE maps to chromosome 11. In a technical comment, Aleister Saunders and colleagues at Massachusetts General Hospital also report that a BACE homolog, which they call BACE2, resides on the obligatory Down's syndrome region of chromosome 21. In response, Fan et al. report that experiments using BACE antisense oligonucleotides in HEK 293 cells suggest that BACE2 is unlikely to be the principal β-secretase, at least not in these cells.
Saunders AJ, Kim T-W, Tanzi RE. BACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down’s syndrome region of chromosome 21. Science 1999 Nov 12;(286):1255a. Full text (subscribers only).
Fan W, Bennett BD, Babu-Kahn S, Yi L, Louis J-C, McCaleb M, Citron M, Vassar R, Richards WG. Reply to above. Science 1999 Nov 12;(286):1255a.
No Available Further Reading
- Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. PubMed.