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J. Biol. Chem., Vol. 280, Issue 19, 18755-18770, May 13, 2005

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Statins Cause Intracellular Accumulation of Amyloid Precursor Protein, -Secretase-cleaved Fragments, and Amyloid -Peptide via an Isoprenoid-dependent Mechanism^*

Sarah L. Cole, Aneta Grudzien, Ingrid O. Manhart, Brent L. Kelly, Holly Oakley, and Robert Vassar

From the Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611

The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and nonsterol isoprenoids), as a therapy for Alzheimer 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 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 amyloid precursor protein (APP) metabolism and amyloid -peptide (A) genesis are unknown. In this 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 disease, we analyzed statin effects on both secreted and cell-associated A. As reported previously, 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 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.

Received for publication, December 9, 2004 , and in revised form, February 8, 2005.

Note Added in Proof—While this manuscript was in review, Pedrini et al. reported that statins modulate -secretase processing of APP by ROCK in an isoprenoid-dependent manner (PLoS Medicine (2005) 2, 1–13). In the current study, we did not directly investigate the potential role of ROCK in mediating the effects that we observed, and further research will be required to determine the relationships between our results and those of Pedrini et al.

^* This work was supported by Grant 53280004 from the Illinois Department of Public Health, Office of Health Promotion, and Grant IIRG-02-4282 from the Alzheimer's Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-3700; Fax: 312-503-7912; E-mail: s-cole4{at}northwestern.edu. To whom correspondence may be addressed: Dept. of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-3361; Fax: 312-503-7912; E-mail: r-vassar{at}northwestern.edu.

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