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J. Biol. Chem., Vol. 282, Issue 37, 26832-26844, September 14, 2007

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Statins Reduce Amyloid- Production through Inhibition of Protein Isoprenylation^*

Stephen M. Ostrowski¹, Brandy L. Wilkinson, Todd E. Golde, and Gary Landreth²

From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and theDepartment of Neuroscience, Mayo Clinic Jacksonville, Mayo Clinic College of Medicine, Jacksonville, Florida 32224

Epidemiological evidence suggests that long term treatment with hydroxymethylglutaryl-CoA reductase inhibitors, or statins, decreases the risk for developing Alzheimer disease (AD). However, statin-mediated AD protection cannot be fully explained by reduction of cholesterol levels. In addition to their cholesterol lowering effects, statins have pleiotropic actions and act to lower the concentrations of isoprenoid intermediates, such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate. The Rho and Rab family small G-proteins require addition of these isoprenyl moieties at their C termini for normal GTPase function. In neuroblastoma cell lines, treatment with statins inhibits the membrane localization of Rho and Rab proteins at statin doses as low as 200 nM, without affecting cellular cholesterol levels. In addition, we show for the first time that at low, physiologically relevant, doses statins preferentially inhibit the isoprenylation of a subset of GTPases. The amyloid precursor protein (APP) is proteolytically cleaved to generate -amyloid (A), which is the major component of senile plaques found in AD. We show that inhibition of protein isoprenylation by statins causes the accumulation of APP within the cell through inhibition of Rab family proteins involved in vesicular trafficking. Moreover, inhibition of Rho family protein function reduces levels of APP C-terminal fragments due to enhanced lysosomal dependent degradation. Statin inhibition of protein isoprenylation results in decreased A secretion. In summary, we show that statins selectively inhibit GTPase isoprenylation at clinically relevant doses, leading to reduced A production in an isoprenoid-dependent manner. These studies provide insight into the mechanisms by which statins may reduce AD pathogenesis.

Received for publication, March 27, 2007 , and in revised form, July 16, 2007.

^* This work was supported in part by grants from the Alzheimer's Association and the Blanchette Hooker Rockefeller Foundation. 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.

¹ Supported in part by National Institutes of Health Grant T32 GM07250 to the Case Medical Scientist Training Program.

² To whom correspondence should be addressed: 10900 Euclid Ave., Case School of Medicine, Rm. E504, Cleveland, OH 44106. Tel.: 216-368-6101; E-mail: gel2{at}case.edu.

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