Read with caution!
This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.
A few months ago, I saw this video, in which Salman Khan interviews a dude who’s really into statins:
Here’s a representative sample of dialogue:
Salman Khan: “What about statins? I mean… these are drugs like Lipitor and Crestor and, so, so, I mean, would you, I mean, I, I, no one should take our medical advice based on a thing in a video–
Dr. Agus: “Right.”
Salman Khan: “–but, I mean, is it, are people taking it just for heart disease or are people taking it more broadly now?”
Dr. Agus: “Listen, I mean, I’m a believer that these drugs have such a profound effect on cancer, heart disease, stroke, potentially Alzheimer’s, that you should consider taking it to prevent these diseases. And again, giving no recommendations, but what I say is, you, your parents, you should talk with your doctor: why shouldn’t I be on this drug?”
So wait, you’re saying you do like statins or you don’t like statins?
Statins are drugs that inhibit cholesterol synthesis. Atorvastatin, better known as Lipitor (though it went off patent last year), is by far the best-selling drug of all time. Statins are usually prescribed to reduce the incidence of heart disease in people with high cholesterol, though Dr. Agus asserts the effect is actually because statins reduce inflammation, which in turn reduces heart disease (even in people without high cholesterol) and cancer and maybe other stuff. Many Khan Academy users (see comments) were a bit amused and/or put off by the commercial tone of the video. Nevertheless, ever since realizing what boundless pro-statin enthusiasm exists in the world, I’ve been waiting to hear the claim that statins also prevent prion disease.
I finally ran across such claim while writing the cpd-B post, as Doh-Ura mentioned that simvastatin (commercially, Zocor) had been shown to delay prion disease onset and might be used in conjunction with cpd-B. Here is a quick at-a-glance summary of some studies that tested statins on prion disease models:
|Mok 2006||simvastatin||100 mg/kg||mice infected with 139A||16-20 days||9-10%||survival|
|Kempster 2007||simvastatin||1 mg/kg||mice infected with ME7||10 days||5%||survival|
|Haviv 2008||simvastatin||2 – 20 mg/kg||mice infected with RML||19-22 days||~10%||onset of symptoms|
|Vetrugno 2009||pravastatin||200 mg/kg||mice infected with 139A||17 days||10%||survival|
Going in, the earlier authors cited in vitro evidence that prion disease depends upon lipid rafts, which are cholesterol-rich parts of the plasma membrane, and that statins might therefore delay the disease by depleting cholesterol. For instance, Haviv writes:
PrPC is attached to membranes through its glycosylphosphatidylinositol (GPI) anchor, which localizes PrPC to specific membrane microdomains enriched with cholesterol and sphingomyelin, known as lipid rafts… Several lines of evidence implicate lipid rafts in the conversion of PrPCto PrPSc. Specifically, PrPC and PrPSc colocalize to rafts, and cholesterol depletion from rafts decreases PrPSc formation in prion-infected cell lines. The localization into lipid rafts is important for PrPC conversion.
Yet at the end, all four studies reported that statins’ effects on cholesterol were not the mechanism of action. In fact, the drugs were mostly reported to have absolutely no effect on levels of cholesterol in the brain. Even more curiously, inhibiting PrPSc formation or aggregation was also not the mechanism of action. In fact, Haviv actually reported increased levels of PrPSc in the treatment group. Haviv concludes the drug was neuroprotective in some other way that allowed the neurons to withstand a greater amount of PrPSc before dying, thus outlasting their untreated counterparts.
So how do statins delay scrapie onset? Haviv did an experiment adding mevalonate to the mice’s diet and found this abolished the beneficial effect of statins, thus zeroing in on the source of the effect– Vetrugno summarizes Haviv’s results thus:
Noteworthily, they demonstrated that the pharmacological effect in their model was mediated through the L-mevalonate pathway, i.e. probably by preventing isoprenylation of signalling molecules, as the beneficial effect of statin on survival was reversed completely by the administration of mevalonate to the mouse diet. Thus, further studies are indeed needed to clarify the precise relationship among cholesterol metabolism, PrPC/PrPScconversion and statin pharmacological action in the brain.
But this is still quite an upstream, holistic sort of explanation. How does preventing isoprenylation of signalling molecules delay prion disease without reducing PrPSc?? We just don’t know. Vetrugno also refers to the “pleiotropic” effects of statins (which I read as: hand-waving; “they do lots of stuff”) and points to preliminary results indicating that statins also help with Parkinson’s and Alzheimer’s. Dr. Agus would love it
update 2012-12-13: Kumar 2008‘s findings may shed additional light on how statins work in prion disease. Kumar found that expression of ABCA1 – a major regulator of cellular cholesterol levels – appears to play an important role in prion disease. Abca1 expression is found to be elevated in prion-infected cell culture and in the brains of mice infected with RML prions. Meanwhile, in ScN2a cell culture, artificially overexpressing ABCA1 increases PrPSc conversion while knocking down ABCA1 reduces PrPC levels and PrPSc conversion. This provides some possible insight into the why statins might be effective in prion disease:
Although ABCA1 transports cholesterol to lipoprotein acceptors, increased expression of ABCA1 also can cause a general increase in membrane cholesterol. Once cholesterol is in membrane, it is distributed non-uniformly by lateral diffusion and condensation into cholesterol-rich CLD, which do not provide cholesterol for efflux to apolipoproteins (Mendez et al., 2001). Under this scenario, our demonstration that increased ABCA1 enhances PrPSc formation might be explained by an increased supply of PrPC due to more or larger CLD that serve as sites for the GPI-anchored protein. Since Prnp gene expression was not affected by changes in ABCA1 levels, increased membrane cholesterol and CLD may enhance cell surface localization and stability of PrPC.
update 2013-05-24: I’ve also posted a more thorough review of these studies here: A comparison of statin studies in scrapie-infected mice