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Isoprenoids and Related Pharmacological Interventions: Potential Application in Alzheimer’s Disease

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Abstract

Two major isoprenoids, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, serve as lipid donors for the posttranslational modification (known as prenylation) of proteins that possess a characteristic C-terminal motif. The prenylation reaction is catalyzed by prenyltransferases. The lipid prenyl group facilitates to anchor the proteins in cell membranes and mediates protein–protein interactions. A variety of important intracellular proteins undergo prenylation, including almost all members of small GTPase superfamilies as well as heterotrimeric G protein subunits and nuclear lamins. These prenylated proteins are involved in regulating a wide range of cellular processes and functions, such as cell growth, differentiation, cytoskeletal organization, and vesicle trafficking. Prenylated proteins are also implicated in the pathogenesis of different types of diseases. Consequently, isoprenoids and/or prenyltransferases have emerged as attractive therapeutic targets for combating various disorders. This review attempts to summarize the pharmacological agents currently available or under development that control isoprenoid availability and/or the process of prenylation, mainly focusing on statins, bisphosphonates, and prenyltransferase inhibitors. Whereas statins and bisphosphonates deplete the production of isoprenoids by inhibiting the activity of upstream enzymes, prenyltransferase inhibitors directly block the prenylation of proteins. As the importance of isoprenoids and prenylated proteins in health and disease continues to emerge, the therapeutic potential of these pharmacological agents has expanded across multiple disciplines. This review mainly discusses their potential application in Alzheimer’s disease.

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Acknowledgments

This work was supported in part by grants from the National Institutes of Health (AG031846), the Alzheimer's Association (IIRG-09-131791, the American Health Assistance Foundation (A2010328), and the Academic Health Center of the University of Minnesota.

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  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, 2001 6th St SE, MTRF 4-208, Minneapolis, MN, 55455, USA

    Ling Li, Wei Zhang, Shaowu Cheng, Dongfeng Cao & Marc Parent

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Li, L., Zhang, W., Cheng, S. et al. Isoprenoids and Related Pharmacological Interventions: Potential Application in Alzheimer’s Disease. Mol Neurobiol 46, 64–77 (2012). https://doi.org/10.1007/s12035-012-8253-1

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