Despite the problems with chemical tractability, β-secretase (BACE) remains one of the most promising targets for the treatment of Alzheimer's disease. It has been known for some time that APP, BACE, and γ-secretase (presenilins and associated proteins) all localize, at least partially, to membrane domains enriched in cholesterol called rafts. This is of interest because the statins, blockbuster drugs that lower cholesterol, inhibit the generation of Aβ peptides in cultured cells. Kai Simons and coworkers have proposed that APP inside rafts may be "bad" because it is mainly cleaved by β-secretase, whereas APP outside rafts may be "good" because it is mainly processed by α-secretase. Cordy et al. provide additional evidence for this hypothesis. They demonstrate an increase of Aβ secretion upon transfection of cells with a BACE construct targeted to rafts by an artificial GPI anchor. Lovastatin treatment abolishes this increase. The current study was performed in a neuroblastoma cell line, but the effects of protein sorting may be even more severe in a mature neuron where transport...  Read more

Despite the problems with chemical tractability, β-secretase (BACE) remains one of the most promising targets for the treatment of Alzheimer's disease. It has been known for some time that APP, BACE, and γ-secretase (presenilins and associated proteins) all localize, at least partially, to membrane domains enriched in cholesterol called rafts. This is of interest because the statins, blockbuster drugs that lower cholesterol, inhibit the generation of Aβ peptides in cultured cells. Kai Simons and coworkers have proposed that APP inside rafts may be "bad" because it is mainly cleaved by β-secretase, whereas APP outside rafts may be "good" because it is mainly processed by α-secretase. Cordy et al. provide additional evidence for this hypothesis. They demonstrate an increase of Aβ secretion upon transfection of cells with a BACE construct targeted to rafts by an artificial GPI anchor. Lovastatin treatment abolishes this increase. The current study was performed in a neuroblastoma cell line, but the effects of protein sorting may be even more severe in a mature neuron where transport has to occur over very long distances. Hence, it would be interesting to study the effect of the GPI-BACE in a transgenic mouse.

View all comments by Gerard Drewes

I think this issue is worth exploring,but I am concerned that the ability of a GPI-BACE chimera to cleave APP may be too artificial a model to tell us much about how the authentic BACE behaves. GPI-linked peptides would be expected to partition in rafts or raft-like domains. The studies of the Simons group also claim that an endocytosis reaction is important for BACE function, a point not considered by Cordy et al.

View all comments by Vincent Marchesi

Increasing evidence from biochemical, epidemiological, and genetic studies links cholesterol levels to Aβ production and the onset of AD pathology. Total cellular cholesterol can regulate Aβ generation, as evidenced by decreased Aβ levels in cells treated with statins, which inhibit cholesterol intake and synthesis. Intracellular distribution and/or trafficking of cholesterol are also gaining more and more support as potentially valid targets for indirect antiamyloid therapy. Altered cholesterol trafficking through the Niemann-Pick C1 compartment and altered cholesterol distribution into cholesteryl-ester droplets and lipid rafts, all affect APP processing into Aβ. Anthony Turner, Joanna Cordy and colleagues show that targeting BACE1 to lipid rafts is sufficient to elevate secreted Aβ levels, further strengthening the relevance of intracellular compartmentation of cholesterol in Aβ generation. Although Kai Simons and colleagues, Kumar Sambamurti and colleagues, and others have previously shown that lipid rafts are important players in at least BACE1-mediated processing of APP,...  Read more

Increasing evidence from biochemical, epidemiological, and genetic studies links cholesterol levels to Aβ production and the onset of AD pathology. Total cellular cholesterol can regulate Aβ generation, as evidenced by decreased Aβ levels in cells treated with statins, which inhibit cholesterol intake and synthesis. Intracellular distribution and/or trafficking of cholesterol are also gaining more and more support as potentially valid targets for indirect antiamyloid therapy. Altered cholesterol trafficking through the Niemann-Pick C1 compartment and altered cholesterol distribution into cholesteryl-ester droplets and lipid rafts, all affect APP processing into Aβ. Anthony Turner, Joanna Cordy and colleagues show that targeting BACE1 to lipid rafts is sufficient to elevate secreted Aβ levels, further strengthening the relevance of intracellular compartmentation of cholesterol in Aβ generation. Although Kai Simons and colleagues, Kumar Sambamurti and colleagues, and others have previously shown that lipid rafts are important players in at least BACE1-mediated processing of APP, the new study by Cordy et al. elegantly employs recombinant GPI-anchored BACE1 to show that mislocalization of BACE1 alone to lipid rafts is sufficient to elevate Aβ generation in a neuroblasoma cell line. Whether this is a saturable increase or all APP contained in lipid rafts is necessarily processed by BACE1 remains to be established. Interestingly, APP695 was shown in this study to be a better substrate for GPI-anchored BACE1 processing than APP751. The authors attribute this effect to differential compartmentation of the APP isoforms, but it would also be interesting to speculate on potential activities of the KPI/OX-2 domains in lipid rafts.

View all comments by Dora M. Kovacs