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Papers In Press, published online ahead of print February 17, 2005
Department of Cellular and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611
Corresponding Author: r-vassar{at}northwestern.edu
The use of statins, HMG CoA reductase inhibitors that block the synthesis of mevalonate (and down-stream products such as cholesterol and non-sterol isoprenoids), as a therapy for Alzheimer’s Disease is currently the subject of intense debate. It has been reported that statins reduce the risk of developing the disorder, and a link between cholesterol and Alzheimer’s Disease pathophysiology has been proposed. Moreover, experimental studies, focusing on the cholesterol-dependent effects of statins, have demonstrated a close association between cellular cholesterol levels and amyloid production. However, evidence suggests that statins are pleiotropic, and the potential cholesterol-independent effects of statins on APP metabolism and A
J. Biol. Chem, 10.1074/jbc.M413895200
Submitted on December 9, 2004
Revised on February 8, 2005
Accepted on February 17, 2005
Statins cause intracellular accumulation of APP,
-secretase cleaved fragments, and A via an isoprenoid-dependent mechanism
genesis are unknown. In the current study, we developed a novel in vitro system that enabled the discrete analysis of cholesterol-dependent and -independent (i.e. isoprenoid-dependent) statin effects on APP cleavage and A formation. Given the recent interest in the role that intracellular A may play in Alzheimer’s Disease, we analyzed statin effects on both secreted and cell-associated A. As previously reported, low cellular cholesterol levels favored the 
-secretase pathway and decreased A secretion presumably within the endocytic pathway. In contrast, low isoprenoid levels resulted in the accumulation of APP, amyloidogenic fragments, and A likely within biosynthetic compartments. Importantly, low-cholesterol and low-isoprenoid levels appeared to have completely independent effects on APP metabolism and A formation. Although the implications of these effects for Alzheimer’s Disease pathophysiology have yet to be investigated, to our knowledge these results provide the first evidence that isoprenylation is involved in determining levels of intracellular A.
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