Further Lessons To Understand Better Statins And Cell-Dependent Effects In The Brain

Saturday, 12 December 2009 00:00

Reports on the effectiveness of the use of statins in Alzheimer’s disease, though controversial, could encourage researchers to understand better the effects of statins on the brain, which are less well understood than their effects on other target organs, rather than justify a discontinuation of the research.

In recent decades, the large body of evidence on the effectiveness of the use of statins in decreasing the risk of cardiovascular disease has persuaded researchers to evaluate the use of such drugs in other pathological conditions. Alzheimer’s disease (AD) in fact has been considered as an area for the use of statins. So far data are controversial: some studies suggest that the use of statins is associated with lower risk of other diseases, including dementia due to AD (Arch Neurol 2002; 59:223-7; Neuroepidemiology 2004; 23:94-98). On the other hand, other studies show mixed results from the use of statins in AD patients, thus decreasing interest in conducting studies to evaluate the effectiveness of such drugs in the treatment or prevention of AD (Neurology 2002; 59:1257-8; Int J Neuropsychopharmacol 2001; 4:127-30; Arch Neurol 2003; 60:510-15;  Am J Alzheimers Dis Other Demen 2004; 19: 275-78).  It has also been shown that statins induce significant DNA damage in neuronal cells in vivo (Food Chem Toxicol 2008; 46:3186-92). Other studies reported activation of both pro- and anti-inflammatory pathways, increased cell death, and higher susceptibility to oxidative damage in brain tissue or brain cells exposed to statins (J Neurosci res 2005; 79:340-50;Brain res 2006; 1104:27-38; J Neurosci Res 2008; 86:603-9). The controversial reports, should not justify a discontinuation of the research in that direction, but rather encourage researchers to understand better the effects of statins on the brain, which are less well understood than their effects on other target organs. Some patients develop symptoms of dementia as a result of statin therapy, which improve or disappear upon statin withdrawal. The cognitive impairment associated with some statins is rarely reported as an adverse effect of statin therapy, and is attributed instead as an age- rather than a therapy-related issue, particularly in the elderly. (Pharmacotherapy 2003; 23: 1663-67; Pharmacotherapy 2003; 23: 871-80).
The mechanisms governing the crossing of the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier by such drugs need to be understood better. Simvastatin, a lipid-soluble statin that easily crosses the BBB, and pravastatin, a hydrophilic statin, which does not readily cross the BBB, have differential effects on some AD-related markers in human CSF, such as Tau phosphorylated at Thr-181 (pTau _Thr181), phospholipid transfer protein (PLTP) activity, and levels of CSF apolipoprotein E (apoE) (J Alzheimersm Dis 2006; 9: 1-12;Dement Geriatr Cogn Disord 2006; 22: 392-98). The differences in these two statins and their abilities to cross the BBB, as well as observed differences in their intra-thecal availability, could produce different effects on the brain cells.
The same scientific group led by John Albers (J Lipid Res 2009; 50:2095-102) compared the effects of the two statins, simvastatin and pravastatin, on primary human astrocytes and neuroblastoma cells and assessed the effects of simvastatin and pravastatin on expression of ABCA1(*), APOE, PLTP, microtubule-associated protein Tau (MAPT), and some of the genes related to Tau phosphorylation, disabled 1 (DAB1), cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3beta1(GSK3beta1), and amyloid precursor protein (APP): genes functionally associated with AD. By directly applying the drugs to cells, instead of administering them to animals, it is possible to eliminate issues of blood-brain barrier transfer as a reason for any differing effects.  Albers and colleagues looked at the expression of genes related to neurodegeneration, and found that, despite using biologically equivalent drug concentrations, differences were seen both between cells and between drugs.  Simvastatin reduced the expression of the cholesterol transporter ABCA1 by approximately 80% in astrocytes, while pravastatin had an attenuated effect, lowering expression by around 50%. Another difference was that while both statins decreased expression of the Tau protein in astrocytes, they increased Tau expression in neurons; pravastatin also increased the expression of another Alzheimer’s hallmark, APP. The study indicates that simvastatin and pravastatin had differential effects on expression of genes relevant for AD development and that these effects are dependent not only on the type of statin but also on cell type. Generally, astrocytes were less susceptible to statin effect, probably due to a greater resilience in changes of cholesterol levels in response to statin treatment.
Some of the messages to be taken from the research of John Albers and colleagues are as follows.
“… The use of statins needs to be evaluated on an individual basis and carefully monitored for potentially detrimental effects of statins on the brain… The effects of statins on expression of genes involved in neurodegenerative processes are statin and cell dependent… Brain cholesterol levels tend to be reduced in elderly people, and in such individuals the long-term effects of statin therapy could lead to transient or permanent cognitive impairment…The potential mechanism involved in development of statin-induced cognitive impairment in vulnerable patients requires further understanding” (J Lipid Res 2009; 50:2095-102).

December 12, 2009

(*)ABCA1 =ATP-binding cassette transporter. ABCA1 is member 1 of human transporter sub-family ABCA also known as the cholesterol efflux regulatory protein (CERP): it is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipids  homeostasis (Genomics 1994; 21:150-9).

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