. Statins reduce amyloid-beta production through inhibition of protein isoprenylation. J Biol Chem. 2007 Sep 14;282(37):26832-44. PubMed.

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  1. Statins on the Brain
    This paper by Gary Landreth’s group casts important new light on the regulation of APP processing by statins and the actions of statins on small GTPases. Previous data demonstrate that statins inhibit APP processing. The mechanism is thought to be mediated by isoprenylation. When HMG-CoA reductase is inhibited by more than 90 percent, the amount of substrate flowing through the cholesterol synthetic pathway decreases to a point where isoprenylation also decreases because of decreases in geranylgeranyl pyrophosphate and farnesylfarnesyl pyrophosphate. Because small GTPases such as Rac and Rho need isoprenylation to associate with membranes, their activity declines.

    Landreth’s team has now investigated this issue in more detail. They make the striking observation that the sensitivity of GTPases to statins differs depending on the GTPase. Cdc42 is highly sensitive, Rac and Rab1b GTPases are moderately sensitive, and Rab4/5b GTPases are relatively insensitive. The mechanism underlying these differences might lie in differential sensitivity or distribution of geranylgeranyl and farnesylfarnesyl transferases (1). Clearly, there is much to be investigated. The differential sensitivity is important for two reasons. The first point to note is that simvastatin reaches a concentration in the brain of about 300-500 nM (this is a new figure provided by Gibson Wood’s team) (2). Rac and Rab1b both respond to 200 nM simvastatin, but Rab4 and Rab5b do not. The second point to note is that Rho GTPases regulate APP processing; previous reports suggest that Rab1b specifically regulates APP processing, which suggests that it should be possible to inhibit APP processing with statins at doses that might not impair other cellular functions (3,4).

    These data open up a number of new avenues for understanding the regulation of APP and should provide new and useful tools for modulating APP processing. I can’t resist putting in one clinical note about this issue, though. I recently published a study indicating that simvastatin is associated with similar reductions in both dementia and Parkinson disease (5). If we assume that the reductions are real and occur through similar mechanisms in both diseases, then the data suggest that the mechanism is not mediated by inhibiting Aβ accumulation because Aβ has not been implicated in the pathophysiology of Parkinson disease. These results are consistent with findings by several investigators indicating that statin use is not associated with a reduction in Aβ levels in CSF. So, statins might be very useful in the arsenal of medications used to manage neurodegenerative disease, but whether the mechanism of action involves changes in APP metabolism is subject to debate.

    References:

    . Differential prenylation of proteins as a function of mevalonate concentration in CHO cells. Arch Biochem Biophys. 1993 Mar;301(2):210-5. PubMed.

    . Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther. 2005 Feb;312(2):786-93. PubMed.

    . Retention of the Alzheimer's amyloid precursor fragment C99 in the endoplasmic reticulum prevents formation of amyloid beta-peptide. J Biol Chem. 2001 Jun 8;276(23):20267-79. PubMed.

    . Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem. 2005 May 13;280(19):18755-70. PubMed.

    . Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.