Alzheimer's disease, which is associated with the generation of amyloid-β peptide (Aβ), has been linked to lipid regulation. However, the cellular mechanisms that link Aβ to lipid metabolism have been poorly understood. Now, a report in Nature Cell Biology provides, for the first time, a functional basis for the relationship between lipids and Alzheimer's disease.
The precursor of Aβ, amyloid precursor protein (APP), is first cleaved by β-secretase, and subsequently by γ-secretase to produce Aβ40 and Aβ42. Depletion of cholesterol has been linked to a decrease in γ-secretase activity and a resulting decrease in Aβ. The authors first looked at presenilin 1 and 2 (PS1 and PS2), either of which can function as the active centre of the γ-secretase complex. Mouse embryonic fibroblasts (MEFs) that lack PS1 and PS2 showed an increase in their levels of cholesterol and sphingomyelin, whereas wild-type neurons in which γ-secretase was inhibited showed a rise in sphingomyelin levels that was accompanied by a drop in sphingomyelinase (SMase) activity.
To analyse the effect of sphingomyelin on Aβ levels, Grimm et al. inhibited SMase in neurons, and noted a rise in sphingomyelin and a decrease in the levels of intracellular and secreted Aβ. In MEFs that lacked APP and Aβ precursor-like protein 2 (APLP2), the levels of sphingomyelin, SMase and cholesterol were similar to those in cells lacking presenilin or γ-secretase activity. Inhibition of γ-secretase in these App−/−;Aplp2−/− cells did not alter cholesterol levels, which indicates that the cleavage products of APP and APLP2 are responsible for the change in lipid levels. To determine whether Aβ, the most prominent cleavage product, mediates this effect, the authors looked at the specific metabolic pathways of cholesterol and sphingomyelin.
In App−/−;Aplp2−/− MEFs, SMase activity was low, but could be restored to partial wild-type levels by the addition of Aβ-containing media. Indeed, homogenates of App−/−;Aplp2−/− MEFs showed enhanced SMase activity on addition of synthetic Aβ. Further in vitro experiments showed that Aβ42 specifically affects SMase, whereas Aβ40 is specific for hydroxymethylglutaryl-CoA reductase (HMGR), which is involved in cholesterol metabolism.
The authors propose a model in which an enzymic cascade of γ-secretase, APP processing and Aβ can affect cholesterol and sphingomyelin metabolism, resulting in altered levels of these lipids, which, in turn, regulates Aβ levels. The authors concede that additional cleavage products of APP other than Aβ might be involved. The functional basis of the link between Aβ and lipid levels has direct relevance to Alzheimer's disease and, as the authors suggest, “may provide a rational basis for therapy”.
ORIGINAL RESEARCH PAPER
Grimm, M. O. et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nature Cell Biol. 7, 1118–1123 (2005)
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Ross, H. The lipid connection. Nat Rev Neurosci 6, 912 (2005). https://doi.org/10.1038/nrn1817