One of the primary problems with the use of statins is that they possess "pleiotrophic" effects--too many biological functions depend upon, or are related to, cholesterol and /or the mavelonate pathway that is blocked by statins (HMG-CoA reductase inhibitors). On the positive side, statins are very powerful anti-inflammatory agents and are able to wonderously increase perfusion everywhere . Their short term use immediately post heart attack seems to be of unquestionable use. but to take this medication for life?

At present, research is underway determining if statins could be utilized for immunosuppression due to the effect upon T-cell suppression. and also as a cancer chemotherapeutic agent, due to statins' effects upon the small GTPases (Rho, Ras, Rab)-- statins interfere with prenylation of these translational proteins. I will make the glib observation that if you are planning on a transplant or developing cancer, possibly statins are a good bet (though the original Pravachol trial "CARE" found a 1200% relative increase in breast cancer in the women in their trial--this statistic was deemed "an anomoly" due to the fact that the placebo group only had 1 incident, a # less than expected, though increases in cancer have been found in statin treatment groups from many other studies, esp. in elderly (>70 yrs) males.

Cholesterol has recently been found to be ESSENTIAL to the neuronal synapses in the brain and
ApoE is the most abundant apolipolipid in the brain and delivers cholesterol to the neurons. (studies with statins and alzheimer's utilizing statins to decrease ApoE4 are Still underway. Problem with these studies is that initially one would expect some benefit from statins due to their anti inflammatory effects, but IF they ran long enough (ie >5 ys) any effects w/ depletion of cholesterol would be evident. Cholesterol is made de novo in the brain itself; cholesterol cannot cross the blood brain barrier, so the brain has its own mavelonate pathway to its production. and fortunately, brain cholesterol has a VERY LONG HALF LIFE--5 yrs. any studies that last <5yrs (almost ALL pharmaceutical studies) will not pick up the effects of lowered brain cholesterol and ApoE. Recently, Alzheimer's reserach has been shifting toward increases in tau phosphorylation as etiopathogenic in Alzheimer's--and statins increase tau phosphorylation. statins are studied in alzheimer's because they specifically decrease ApoE--the substance responsible for transporting cholesterol to the neurons for synaptic functions to occur. with the newest information that Apoe is essential for neuronal synapses, manipulating cholesterol and apoe for alzheimer's seems more than a questionable undertaking.

NEUROBIOLOGY:
Cholesterol--Making or Breaking the Synapse
Ben A. Barres and Stephen J. Smith
Synapses are regions where neurons meet and communicate. But how is their formation regulated in the developing and adult brain? As Smith and Barres explain in their Perspective, the answer could not be simpler. It turns out that, at least in the culture dish, a type of glial cell called an astrocyte produces the molecule cholesterol, which is taken up by neurons and then directs formation of synapses perhaps by regulating vital signaling pathways (Mauch et al.).

Neurons need cholesterol secreted by glial cells to form and maintain functional synapses. And cholesterol is necessary for synaptogenesis and probably for production and transport of vesicles necessary for neurotransmission. If one accepts the concept of neuronal plasticity in the adult brain, then deliberately suppressing cholesterol metabolism in the brain seems questionable.

(to be continued in next post)
madelyn