SECRETORY PROCESSING OF AMYLOID PRECURSOR PROTEIN IS INHIBITED BY INCREASE IN CELLULAR CHOLESTEROL CONTENT

Plasma-membrane composition plays a crucial role in most of the cellul ar functions that depend on membrane processes, In virtually all cell types the proteolytic processing of Alzheimer amyloid precursor protei n (APP) to generate soluble APP (sAPP) is believed to occur at the pla sma membrane or in its immediate proximity. Alteration of this metabol ic pathway has been linked to the pathogenesis of Alzheimer's disease. We analysed the effect of membrane cholesterol enrichment on APP meta bolism. Incubation of COS cells with increasing concentrations of none sterified cholesterol carried by rabbit beta-very low-density lipoprot ein caused a dose-dependent inhibition of sAPP release: 70% inhibition with 10 mu g/ml non-esterified cholesterol. A less pronounced inhibit ory effect was observed on treatment with human low-density lipoprotei n. Inhibition of sAPP release was independent of receptor-mediated lip oprotein metabolism since simultaneous treatment with chloroquine did not modify the effect of lipoprotein treatment. In addition, treatment with cholesterol dissolved in either ethanol or methyl-beta-cyclodext rin elicited the same effect. Excess non-esterified cholesterol did no t cause cell toxicity. Cell cholesterol mass inversely correlated with sAPP release. Progesterone, which inhibits shuttling of nonesterified cholesterol between the plasma membrane and intracellular pools, had no effect on the inhibition of sAPP release from cholesterol-loaded ce lls, providing indirect evidence that cholesterol may act at the plasm a membrane.