05 Apr 2003

A paper in press in the Journal of Biological Chemistry reports that the lipid ceramide may contribute to the formation of amyloid deposits found in Alzheimer's disease patients because it stabilizes BACE, one of the enzymes that cleaves the Aß peptide from its precursor protein (AßPP).

Interest in ceramide, a core component of a major class of lipids called sphingolipids, rose recently when (Xianlin Han ) and colleagues showed that it is elevated early on in AD (see ARF related news story). But if and how the lipid had any major impact on disease progression was unclear—until now.

Luigi Puglielli and colleagues, working with Dora Kovacs at Massachusetts General Hospital, Charlestown, used a variety of methods to measure the effect of ceramide on Aβ production. When the authors added a soluble, active variant of ceramide to either Chinese hamster ovary cells or human neuroglioma cells (which expressed AβPP), the cells responded by significantly increasing production of Aβ and nearly doubling the amount of the peptide released into the cell culture medium. The same happened when the scientists stimulated the cells to release ceramide enzymatically from sphingomyelin. In contrast, when Puglielli et al. treated the cells with an inhibitor of ceramide biosynthesis, cellular levels of the lipid fell by about 70 percent, and secretion of Aβ dropped by half.

Aβ is snipped out of its protein precursor by the sequential action of two proteases—β-site AβPP-cleaving enzyme (BACE) and γ-secretase—the latter acting on two distinct peptide bonds to produce the Aβ40 and Aβ42 variants. Interestingly, altering the amount of ceramide did not affect the Aβ40:Aβ42 ratio, suggesting that γ-secretase is unaffected by the lipid. When Puglielli and colleagues looked at cellular BACE, however, they found that ceramide causes this enzyme to accumulate, reaching maximum levels about threefold higher than normal in about four days. By radioactively labeling the protease, Puglielli was able to follow its decay, reporting that ceramide almost doubles the half-life of BACE to about 30 hours. It is also worth noting that BACE itself was recently shown to be elevated in AD brains (see ARF related news story).—Tom Fagan