Published 6 January 2003. doi:10.1083/jcb1601iti5
© The Rockefeller University Press,
0021-9525/2003/1/6 $5.00
The Journal of Cell Biology, Volume 160, Number 1, 6-6
Rafts and the evil amyloids
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APP (green, bottom) meets ß-secretase (green, top) in lipid rafts (red).
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Lipid rafts are bad news for those with Alzheimer's disease (AD). On page 113, Ehehalt et al. show that formation of the ß-amyloid peptide (Aß), which is tightly linked to AD, depends on the raft association of one of its creators.
The creating enzyme is ß-secretase, which cleaves the amyloid precursor protein (APP) to release a product that is then processed into Aß. Several recent lines of evidence suggest that cholesterol is somehow linked to Aß production. For instance, high cholesterol levels are correlated with an increased likelihood of developing AD.
As cholesterol is found in membrane lipid rafts, the authors investigated whether APP and ß-secretase were linked with these compartments. They found that, indeed, both proteins were found in lipid rafts. Further increasing the fraction of APP and ß-secretase in lipid rafts (by oligomerizing each protein) released more Aß.
The small size of lipid rafts makes it unlikely that both proteins are found within the same raft. The group demonstrates, however, that endocytosis is necessary for Aß formation. Thus, endocytosis may lead to a clustering of rafts that puts ß-secretase within striking distance of APP. The regulation and mechanism of this clustering await further studies.
Decreasing cholesterol levels in cells limited Aß secretion, but how cholesterol is involved is also not yet clear. Perhaps specific lipids are required to activate ß-secretase. The authors plan to use purified secretase and APP to determine whether raft lipids are needed for processing.
Prion scrapies are also formed in lipid rafts, so rafts seem to be conducive to the formation of amyloids. Potential therapeutic drugs should therefore function within raft environments if they are to be successful at preventing amyloid formation. 
Nicole LeBrasseur
lebrasn{at}rockefeller.edu
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