A new study adds support to the theory that a critical first step in the production of the Aβ peptide, i.e., the cleavage of amyloid precursor protein (AβPP) by the BACE enzyme, occurs primarily in specialized, cholesterol-rich areas of the plasma membrane called "lipid rafts." Anthony Turner, Joanna Cordy, and colleagues of the University of Leeds and GlaxoSmithKline Research in Essex, United Kingdom, report in the 30 September issue of PNAS that they were able to boost production of Aβ by directing most of the BACE in the plasma membrane to the lipid rafts.
These findings dovetail with various lines of recent evidence that decreasing cholesterol with statins decreases AD risk, and that increased cholesterol levels boost the production of Aβ in brain (see ARF related news story, and especially the extended comment by Ben Wolozin). Lipid rafts-or more officially, detergent-insoluble glycolipid-enriched membrane domains (DIGs)-differ from the rest of the cell membrane in that their concentrations of cholesterol, glycosphingolipids, and ganglioside lipids are particularly high (see ARF related news story). The rafts act as platforms for an ever-growing number of cellular signaling and trafficking processes.
Interest in rafts in the context of AD arose several years ago, when a number of studies found Aβ, BACE, APP, and PS-1 in the rafts Bouillot et al., 1996; Lee et al., 1998; Simons et al., 1998; Riddell et al., 2001). Reducing cholesterol levels decreases the number of lipid rafts; however, the vast majority of the BACE or APP in the membrane is not found in the rafts. Kai Simons and his colleagues have proposed a model whereby normal membrane conditions favor APP and BACE floating about in the membrane, where BACE is nudged out of the running by the preferred cleavage path of APP, i.e., first by α-secretase and then by γ-secretase, leading to nontoxic peptide products. When age-related changes in membrane conditions (e.g., more cholesterol) increase the number of rafts, APP and BACE find themselves together-and away from the α-secretase-more often, and hence produce more toxic Aβ.
In support of this model, Simons and colleagues recently demonstrated that when APP and BACE are bound together with antibodies in N2A cells, the production of Aβ increases (Ehehalt, et al., 2003). This appeared to be occurring in the rafts, and reducing cholesterol also abolished the Aβ increase. In their current PNAS paper, Turner and colleagues provide further inferential evidence for rafts as the site of the BACE-APP communion in neuroblastoma cells. The researchers anchored BACE to the rafts and substantially boosted the production of Aβ. Again, cholesterol reduction abolished the increase.
In their discussion, the authors bring up the question of the increased incidence of AD with aging. Because cholesterol levels tend to rise during aging, they write, it is conceivable that this increases the opportunities for BACE to interact with APP in lipid rafts, thereby increasing the brain burden of Aβ.—Hakon Heimer
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No Available Further Reading
- Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11735-40. PubMed.