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Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease

Ostrowski, Stephen M
http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
Epidemiological evidence suggests that long term treatment with the cholesterol-lowering HMG-CoA reductase inhibitors, or statins, decreases the risk for developing Alzheimer’s Disease (AD). However, statin-mediated AD protection cannot be fully explained by reduction of cholesterol levels. In addition to their cholesterol lowering effects, statins act pleiotropically 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 moieties for normal protein localization and function. In neuroblastoma cell lines, treatment with statins at high doses inhibits the membrane localization of Rho and Rab proteins, without affecting cellular cholesterol levels. Importantly, we show for the first time that at low, physiologically relevant, doses statins preferentially inhibit the isoprenylation of only a subset of GTPases. In addition, we employ 2D gel electrophoresis to directly monitor the isoprenylated versus non-isoprenylated forms of the proteins, a technique that will be useful for further studies of statin inhibition of protein isoprenylation. The amyloid precursor protein (APP) is proteolytically cleaved to generate beta-amyloid (Aâ), 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 protein geranylgeranylation. Toxin A, a specific and robust inhibitor of Rho family GTPases, has no effects on APP trafficking, suggesting that statins act to inhibit the function of Rho family proteins. In addition, effects of statins on APP trafficking and Aâ production are strikingly similar to those reported previously after the inhibition of Rab1b. Moreover, inhibition of Rho family protein function reduces levels of APP C-terminal fragments (CTFs), resulting in decreased Aâ secretion. We demonstrate that the reductions of CTFs is due to novel regulaton of lysosomal dependent degradation. In summary, we show that statins selectively inhibit GTPase isoprenylation at clinically relevant doses, leading to reduced Aâ production in an isoprenoid-dependent manner. These studies provide insight into the mechanisms by which statins may reduce AD pathogenesis.
Gary Landreth (Advisor)
225 p.
Biology, Neuroscience
Alzheimers Disease; beta-amyloid; statins

Recommended Citations

Citations

  • Ostrowski, S. M. (2008). Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698

    APA Style (7th edition)

  • Ostrowski, Stephen. Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698.

    MLA Style (8th edition)

  • Ostrowski, Stephen. "Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698

    Chicago Manual of Style (17th edition)

case1190669698
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© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.