Cholesterol-Lowering Drugs And Alzheimer S Disease

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1 Future Lipidology ISSN: (Print) (Online) Journal homepage: Cholesterol-Lowering Drugs And Alzheimer S Disease Gunter P Eckert, Walter E Müller & Gibson W. Wood To cite this article: Gunter P Eckert, Walter E Müller & Gibson W. Wood (2007) Cholesterol- Lowering Drugs And Alzheimer S Disease, Future Lipidology, 2:4, To link to this article: Copyright 2007 Future Medicine Ltd Published online: 18 Jan Submit your article to this journal Article views: 50 View related articles Full Terms & Conditions of access and use can be found at

2 REVIEW Cholesterol-lowering drugs and Alzheimer s disease Gunter P Eckert, Walter E Müller & W Gibson Wood Author for correspondence University of Frankfurt, Department of Pharmacology, Biocenter Niederursel, Mari-Curie-Str. 9, D Frankfurt, Germany Tel.: ; Fax: ; g.p.eckert@em.uni-frankfurt.de Experimental in vitro and in vivo findings as well as some retrospective epidemiological studies link cholesterol homeostasis with Alzheimer s disease (AD), and there are some reports suggesting that statins may be efficacious in preventing or treating AD. In vivo and in vitro studies demonstrate that modification of cholesterol levels alters amyloid precursor protein and amyloid β peptide (Aβ) levels but the majority of human data on serum and brain cholesterol levels do not support a role of cholesterol in AD. Moreover, the initial epidemiological reports on statins and AD may have overestimated the extent of protection, since prospective studies and recent meta-analyses show little, if any, support for the efficacy of statins in dementia. This brief but focused review examines support for and against the hypothesis that cholesterol is involved in AD and addresses the issue as to whether statins should be considered for the prevention and treatment of AD. Keywords: Alzheimer s disease, brain, cholesterol, statins part of Cholesterol is a molecule that has captivated scientists for hundreds of years. Obviously it is essential for the propagation of a variety of species and numerous other functions, but malfunction in cholesterol homeostasis can be pathological, most notably in coronary heart disease. Another disease that has been proposed to involve cholesterol is Alzheimer s disease (AD). It has even been suggested that elevated serum cholesterol levels are a risk factor for AD. The role of cholesterol in AD is highly controversial both in terms of being a causative factor and the efficacy of using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in the prevention and treatment of AD. This brief but focused review will examine the role of cholesterol in AD and address whether statins are efficacious in preventing and treating AD. Pharmacological characteristics of statins Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis [1]. The inhibition of HMG-CoA reductase not only prevents cholesterol biosynthesis and induces significant plasma cholesterol reductions [2], but also affects the isoprenoid pathway, which accounts for its pleiotropic effects. Simvastatin and lovastatin are prodrug lactone forms that are transformed to the active acid forms mainly by hepatocytes. Lipophilicity is further characterized by the behavior of compounds on the octanol/water phase. Based on the logarithm of the partition coefficient simvastatin, lovastatin, cerivastatin, fluvastatin, pitavastatin and atorvastatin are lipophilic, while pravastatin is hydrophilic [3]. Rosuvastatin is a relatively new statin, having a polar methane sulphonamide group, and it can be placed between cerivastatin and pravastatin [4]. Lipophilic statins are more susceptible to metabolism by the cytochrome P450 enzyme system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin, which are relatively hydrophilic, are not significantly metabolized by cytochrome P450 enzymes [5,6]. Lovastatin and simvastatin but not pravastatin were detected in the CSF [7]. Active acid forms of simvastatin, lovastatin and pravastatin as well as considerable levels of simvastatin and lovastatin in their lactone forms were determined in mouse brains after a single oral administration [8]. Accordingly, Thelen et al. found that simvastatin and pravastatin were present in the brains of mice, while only simvastatin affected HMG-CoA reductase mrna expression levels [9]. Cholesterol & Alzheimer s disease: in vitro & in vivo studies Neuritic plaques and neurofibrillary tangles in the brain are characteristic neuropathological features of AD. Amyloid-β peptide (Aβ) is a primary component of neuritic plaques. Aβ is amino acid residues long and is derived in part from the transmembrane region of the amyloid-precursor protein (APP) [10]. The initial pathophysiological role of Aβ is widely agreed on [11]. A mounting body of experimental in vitro and in vivo data indicate that brain cholesterol homeostasis is coupled with brain amyloid metabolism, although the mechanism is not / Future Medicine Ltd ISSN Future Lipidol. (2007) 2(4),

3 REVIEW Eckert, Müller & Wood known [12,13]. However, the causative role of cholesterol in the pathogenic cascade of excessive Aβ deposition in the brain of AD patients is not proven. Cell culture studies demonstrate that membrane cholesterol controls the direction of the processing of the APP in vitro [14,15,16,17]. Under similar experimental conditions, reduced Aβ levels were found to increase α-secretase activity [4], suggesting that membrane cholesterol variations are coupled with activity shifting of APP-cleaving secretases [18]. It was further reported that statin-induced decreased release of Aβ was not due to its accumulation in the cell, but rather to decreased formation of Aβ [19]. Cholesterol depletion possibly favors a membrane environment in which β- and γ-secretase cleavage of APP does not efficiently work [18,20]. Parvathy et al. showed that statininduced stimulation of α-secretase was not antagonized by inhibitors of either protein kinase C (PKC) or extracellular signal-regulated kinase (ERK), indicating that PKC and ERK do not play key roles in mediating the effect of statins on APP processing [20]. Moreover, statins changed the transbilayer distribution of cholesterol in synaptosomal plasma membranes, which was correlated with decreased Aβ levels [21,22]. Conversely, cholesterol enrichment of cells enhanced the amyloidogenic processing of membranous APP [14,15], and Aβ peptides affect cellular cholesterol metabolism and intracellular cholesterol distribution [23,24]. Diet-induced hypercholesterolemia resulted in small, but significantly increased total levels of Aβ peptides in the CNS, which were correlated with the levels of both plasma and CNS total cholesterol [25]. This report confirmed earlier findings that rabbits fed a 2% cholesterol-containing diet exhibit an increasing accumulation of intracellular immunolabeled Aβ in the brain [26]. Accordingly, Shie et al. reported significantly higher Aβ immunostained plaque-like deposits in brains of mice harboring the Swedish mutation of human APP fed a high-cholesterol diet [27]. However, another study reported that elevated dietary cholesterol led to significant reduction in brain levels of secreted APP derivatives, including sappα, sappβ, Aβ1 40 and Aβ1 42, while having little to no effect on cell-associated species, including full-length APP and the COOHterminal APP processing derivatives [28]. The underlying mechanisms of these observations are unclear, since strong experimental evidence indicates an independent regulation of peripheral and central cholesterol homeostasis [29,30,31]. One alternative explanation includes effects of plasma cholesterol on vascular pathology, which represents a risk factor for AD [32]. While most of the studies use mice in experiments on cholesterol and Aβ, it is worth noting that significant species differences have to be considered. The biosynthesis rate for cholesterol is approximately 16-fold higher in mice compared with humans [33], and there is also a marked difference in the handling of cholesterol. Mice carry cholesterol mainly in the HDL fraction and the hepatic LDL clearance rate in mice is 40-fold greater than in humans [33,34]. Moreover, inhibition of the mevalonate biosynthesis in mice activates a multivalent feedback regulatory mechanism for HMG-CoA reductase, and this in turn causes an increase in hepatic HMG- CoA reductase [35]. Hence, the majority of studies report that statins are ineffective to reduce serum cholesterol levels in mice [36,30,9,33]. However, Petanceska et al. reported that atorvastatin treatment reduced total serum cholesterol levels by approximately 59%, but had no effect on total brain cholesterol content as determined in cortex and cerebellum [37]. Atorvastatin treatment markedly attenuated Aβ deposition in their PS/APP transgenic mouse model of Alzheimer s amyloidosis [37]. Using guinea pigs, Fassbender et al. showed that high-dose simvastatin treatment reduced Aβ1 40 and Aβ1 42 levels in brain homogenates. Levels of the cholesterol precursor lathosterol but not of total cholesterol levels were reduced in guinea pig brain [17]. Park et al. reported that lovastatin enhanced Aβ production and senile plaque deposition in brains of female TG2596 mice [38]. A recent study by Li et al. demonstrated that simvastatin treatment corrected learning and memory deficits in Tg2576 mice and, more intriguingly, significantly enhanced learning and memory in normal nontransgenic mice. In that study, statin treatment did not affect cerebral Aβ levels, suggesting possible mechanisms that are independent of Αβ/APP metabolism [39]. However, cholesterol levels are predominantly determined using different enzymatic kits; it is worthy to note that due to different methodologies one should be generally cautious in comparing absolute cholesterol levels between different studies. Serum cholesterol levels in humans Elevated serum cholesterol levels have been suggested to increase the risk of developing AD [40]. However, data supporting elevated cholesterol as a risk factor in AD have not been consistently 424 Future Lipidol. (2007) 2(4)

4 Cholesterol-lowering drugs and Alzheimer s disease REVIEW observed. A meta-analysis of ten studies published between 1986 and 1999 found that cholesterol levels were actually significantly lower in AD patients than in control subjects [41]. However, the average difference in cholesterol levels between AD and control subjects was relatively small. Total serum cholesterol levels were not statistically significant between AD and control subjects but it was observed that LDL-cholesterol (LDL-C) was significantly higher and HDL-C was significantly lower in AD patients than control subjects [42]. By contrast, LDL-C levels were reported to not be significantly different in AD patients compared with control subjects [43], but total cholesterol levels were significantly lower in AD patients than control subjects. Although the mean total cholesterol levels were significantly lower, the physiological effects of such small changes are unclear. In a population-based study of elderly African Americans compared with controls, serum cholesterol levels were significantly higher in AD patients without apoe4 alleles but were not significant in AD patients with one or two E4 alleles [44]. In a longitudinal study at the first exam, cholesterol levels were significantly higher in AD patients compared with control subjects but were not significantly different at the second exam [45]. A recent study that compared plasma cholesterol levels with brain amyloid deposition found that plasma cholesterol levels were similar and not significantly different among the groups studied [40]. Further analysis involving logarithmic transformation of the data, nonparametric testing and multiple-regression modeling revealed that amyloid load was correlated with elevated plasma cholesterol in subjects years of age but not in subjects 55 years of age and older. By contrast, an earlier study reported that neuritic plaque load in the neocortex and hippocampus was not associated with total plasma cholesterol levels [46]. However, neuritic plaque load in the neocortex and hippocampus was associated with increasing late-life HDL-C levels but not mid-life HDL-C levels [46]. Even though the specific results of the two studies differ, it is interesting that in both reports AD neuropathology is associated with elevated cholesterol levels. The majority of studies on cholesterol levels have been retrospective. In the well-recognized Framingham study, total serum cholesterol levels were not associated with the risk for AD [47]. Actually, such a conclusion is not surprising when consideration is given to the number of AD patients versus the number of individuals with hypercholesterolemia. The estimated number of patients in the USA with AD is 4.5 million [48] and the estimated number of US adults with cholesterol values of 200 mg/dl and higher is 105 million [49], and of that number 37 million have cholesterol levels of 240 mg/dl or higher. If elevated cholesterol is a risk factor for AD then there should be more individuals with AD. Granted this conclusion is a broad generalization and does not take into account factors such as age differences, lipoprotein profiles and other disorders associated with hypercholesterolemia. Perhaps there is a subset of individuals with elevated cholesterol levels who are at risk for AD. For example, it has been reported that elevated cholesterol levels between 40 and 55 years of age may be predictive of subsequent development of AD [40]. A significant association was ascertained between amyloid load and total serum cholesterol levels in the year-old age group compared with older individuals where no association was observed. Hypercholesterolemia may be more pathological in middle-aged individuals than in older individuals. Interestingly, a recent study found that high cholesterol levels in late life were predictive of a reduced risk of dementia [50]. It was suggested in that study that the timing of cholesterol determination may be an important factor in an association between cholesterol levels and dementia. Brain & CSF cholesterol levels in humans Elevated serum cholesterol levels do not appear to be a risk factor for AD. The same conclusion applies to brain cholesterol levels. Cholesterol levels have been determined in different brain regions and CSF of AD patients compared with control subjects. Cholesterol levels were lower in the temporal gyrus of autopsied brains of AD patients in contrast to control subjects [51]. The cholesterol-to-phospholipid ratio of the temporal gyrus was reduced by 30% in the AD brains and no differences were observed in the cholesterol-to-phospholipid ratio in cerebellum of the two groups. The reduction in the cholesterol-to-phospholipid ratio in the temporal gyrus was attributed to cholesterol because the phospholipid-to-protein ratio was similar in brains of both groups. There was a small but significant increase in frontal cortex gray matter of AD patients (2.65 ± 0.14 mg/g wet tissue weight) with the apoe4 genotype compared with apoe4 control subjects (2.04 ± 0.18) [52]. Cholesterol levels did not differ in hippocampal tissue of AD patients as compared with control 425

5 REVIEW Eckert, Müller & Wood subjects [53]. A recent study reported cholesterol levels were similar in cerebral cortex of AD and control individuals with a small increase in cholesterol levels in the basal ganglia of AD patients compared with control subjects [54]. Cholesterol and its metabolites have also been determined in CSF. Levels of both free and esterified cholesterol were significantly lower in CSF of AD patients than levels in control subjects [55]. Cholesterol levels were lower in CSF of AD patients but were not significantly different when compared with control subjects [56], although another report did find significantly lower CSF cholesterol levels in AD patients [57]. Total CSF cholesterol did not significantly differ between AD patients and control subjects but 24S-hydroxycholesterol levels were significantly higher in CSF of AD patients compared with control subjects, and it was concluded that there was an increased turnover of central cholesterol in AD patients [58]. Results of studies on brain and CSF cholesterol levels in AD patients compared with control subjects are as highly variable as those observed in studies on serum and plasma cholesterol. Hence, changes in bulk-brain cholesterol may not contribute to AD pathogenesis. Perhaps changes in cholesterol levels of AD patients occur in cholesterol domains and not in bulk cholesterol levels [59,13]. Cholesterol is not evenly distributed in cell organelles or even within organelles. We have recently shown in astrocytes that cholesterol levels were higher in the trans- Golgi region than in the cis-medial regions and that Aβ stimulated movement of cholesterol from the cis-medial regions to the trans-region of the Golgi complex [24]. In cell membranes, cholesterol is asymmetrically distributed in the exofacial and cytofacial leaflets (i.e., the transbilayer cholesterol distribution) and this distribution was altered by ApoE expression and isoform [60,61], increasing age [62] and statins [36,22]. Redistribution of cholesterol in the exofacial and cytofacial leaflets alters individual leaflet fluidity and function. Other brain cholesterol domains that could differ in AD patients are lipid rafts and caveole both enriched in cholesterol. There is some evidence that production of Aβ-protein may be associated with lipid rafts [63 66]. Statins have been shown to reduce the raft marker flotillin in murine brains [21]. The point is that there may be important changes in cholesterol homeostasis in AD patients, but such proposed changes are occurring in cholesterol domains in contrast to changes in bulk cholesterol levels. Statins in clinical studies Epidemiological trials indicate that statins significantly decreased the incidence of AD: longterm treatment of patients with coronary heart disease (CHD) treated with lovastatin and pravastatin [67] or simvastatin and pravastatin [68] had lowered the risk of developing AD up to 70% compared with control subjects receiving other anti-atherosclerotic medication. These findings are supported by a subsequent retrospective cohort study [67]. Following covariate adjustments, patients being treated with statins were less likely to have dementia. At follow-up, patients on statins showed improvement on their minimental status examination score compared with a decline in controls [69]. Subsequently, prospective studies were initiated to evaluate the ability of statins to prevent AD. The first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism came from a case-control study on elderly nondemented subjects [70]. However, the reported change of cholesterol, lathosterol and 24S-hydroxysterol levels in the CSF were not associated with altered intrathecal secretion of Aβ [70]. Statin-induced changes in cholesterol, lathosterol and 24S-hydroxycholesterol levels were recently confirmed in blood samples from AD patients [71,72]. The effects of lovastatin on Aβ serum levels were investigated during a double-blind, randomized, placebo-controlled study including human subjects who had elevated LDL-C levels [73]. Serum Aβ levels were measured before and after up to 3 months of treatment. Serum Aβ concentrations were dose-dependently decreased after 3 months of treatment and analysis of variance indicated that treatment was statistically significant [73]. In a 26-week randomized, placebo controlled, double-blind study, effects of simvastatin on cholesterol metabolites and Aβ levels in the cerebrospinal fluid of 24 normocholesterolemic AD patients and 20 controls were tested [74]. Overall, simvastatin did not significantly alter CSF levels of Aβ1 40 and Aβ1 42. In post hoc analysis, however, simvastatin significantly decreased Aβ1 40 levels in the CSF of a small cohort of patients with mild AD. The reduction of Aβ correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected AD patients [74]. Besides the small sample sizes, the reported changes in the aforementioned prospective studies were generally small. 426 Future Lipidol. (2007) 2(4)

6 Cholesterol-lowering drugs and Alzheimer s disease REVIEW In a cohort study, 2798 participants over 65 years of age and free of dementia at baseline were investigated. In this study, statin therapy was not associated with a decreased risk of dementia [75]. In a nested case-control study, the association between statin use and AD adjusted for co-morbid medical conditions was evaluated. In that study, a statistically significant inverse association was observed between statin use and AD [76]. The association between statin therapy and risk of AD in a prospective cohort study with documented statin exposure and incident dementia was assessed. Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD [77]. In a longitudinal study of a largely rural, low-socioeconomic-status, community-based cohort of older persons, the use of lipid-lowering drugs (LLAs) by demented cases and nondemented controls was evaluated. Demented individuals were less likely than their nondemented counterparts to be taking lipid-lowering drugs. It was concluded that the findings reflect the different prescribing patterns by physicians for demented and nondemented patients, or a possible protective effect of these drugs against dementia [78]. To examine the association between the use of LLAs and dementia, adjusting for other markers of health, and to investigate factors associated with LLA use, a cohort study of LLA use and a case-control study of dementia in relation to LLA use was initiated. There was no significant effect in subjects aged 80 years and older. LLA use was associated with a lower risk of dementia, and specifically of AD, in those younger than 80 years [79]. Cross-sectional studies of prevalence and incidence and a prospective study of incidence of dementia and AD reveal that statin use might be less frequent in those with prevalent dementia. However, no association between statin use and subsequent onset of dementia or AD was found [80]. A recent meta-analysis systematically identified relevant studies, and data were abstracted according to predefined criteria. The authors conclude that statin use did not show a beneficial effect of the risk of dementia or AD [81]. Accordingly, another meta-analysis concluded that unless there are important effects achievable with specific statins, a more than modest role for statins in preventing AD appears unlikely [82]. Statins exert neuroprotective effects independent of cholesterol What would appear to be paradoxical is epidemiological data showing that patients taking statins have a lower risk of developing AD as compared with individuals not taking statins [67,83,84] and in vivo and in vitro studies of cholesterol and Aβ-protein (see above). The potential efficacy of statins in reducing the risk of AD may be unrelated to cholesterol biosynthesis. There is a growing recognition that statins have cholesterol-independent effects [85,86]. Recent findings emphasize that inhibition of the isoprenoid-pathway by statins modulates the processing of APP independent of cholesterol (Figure 1) [87,88]. Pleiotropic effects of statins have been described that include for example upregulation of endothelial nitric-oxide synthase expression, anti-inflammatory actions, glucose metabolism or anti-oxidant activity [85,86]. Moreover, pleiotropic effects of statins on gene expression in cerebral cortex of mice were recently reported, demonstrating that statins act on multiple pathways in addition to cholesterol synthesis [8]. These pathways involved apoptosis, neuronal growth, glucose homeostasis, cell motility and differentiation. Thus, effects of statins in brain may be both neuroprotective and regenerative, and could lead to a new direction in understanding the potential therapeutic efficacy of statins in AD [8]. We recently report that simvastatin stimulated Bcl-2 gene expression and protein levels and that reduction of Bcl-2 protein levels eliminated neuroprotection afforded by simvastatin. In addition, the protective actions of simvastatin appear to be a result of the drug s activity in a pathway other than HMG-CoA reductase [89]. Accordingly, chronic simvastatin administration in vivo provided neuroprotection in brain cells isolated from guinea pigs after challenge with a Bcl-2 inhibitor or sodium nitroprusside. Brain cells isolated from simvastatin-treated guinea pigs were significantly less vulnerable to mitochondrial dysfunction and caspase-activation. The ratio of Bax/Bcl-2, being a critical factor of the apoptotic state of cells, was significantly reduced in simvastatin-treated animals. Cholesterol levels in the brain remained unchanged in the simvastatin group [90]. These findings provide one of the potential mechanisms for the purported neuroprotective actions of statins. Conclusion There is a paradox generally between the experimental studies and the clinical data on the role of cholesterol in AD. On one hand, the majority of 427

7 REVIEW Eckert, Müller & Wood Figure 1. Potential neuroprotective effects of statins. APP 3 Secretases Aβ APPsα Lipid rafts 2? 4 5 Cholesterol Isoprenoids Bcl-2 Mevalonate Bax Mitochondrion 1 HMG-CoA Cytochrome Caspases Apoptosis Plasma membrane (1) Statins inhibit the rate-limiting enzyme of the cholesterol- and isoprenoid-biosynthesis, which converses HMG-CoA to mevalonate. (2) Reducing cholesterol levels enhances plasma membrane fluidity and decreases lipid raft formation. Lipid rafts are cholesterol-enriched membrane micro-domains, which harbor APP. (3) Accordingly, β- and γ-secretase cleavage of APP is diminished and α-secretase cleavage of APP is amplified. The first pathway leads to the formation of the neurotoxic Aβ, while the latter one creates APPsα that exerts neurotrophic effects. (4) Complementarily, inhibition of the isoprenoid-pathway by statins modulates the processing of APP independently of cholesterol. (5) Recent detected neuroprotective effects of statins involve the upregulation of the anti-apoptotic Bcl-2 protein. Bcl-2 prevents mitochondria from the interactions of Bax. Interaction of Bax with mitochondria promotes the release of cytochrome C and initiates a cascade of events, for example activation of caspases, which finally leads to apoptosis. APP: Amyloid precursor protein. in vivo and in vitro studies show an interaction between cholesterol and Aβ. Much of the clinical data however, do not support involvement of elevated cholesterol levels as a causative factor in AD. Even in the experimental studies, precisely how cholesterol is altering Aβ levels is not known. Clinically, there may be a subgroup of individuals, for example those exhibiting the metabolic syndrome in which elevated cholesterol levels and unidentified cofactor(s) are involved in the development of AD. Finally, the efficacy of statins whether in prevention or treatment of AD is not proven due to inconsistent findings. However, the long-term prevention data look promising. Future perspective Discovering how statins are stimulating antiapoptotic genes will offer new insight into the potential use of other cholesterol-lowering and lipid-related drugs that might have neuroprotective efficacy in specific neurodegenerative diseases and conditions outside of brain in which programmed cell death has been implicated. Acknowledgements This study was supported by the Hanna Bragard-Apfel Foundation and grants from the National Institutes of Health AG-23524, AG and the Department of Veterans Affairs. 428 Future Lipidol. (2007) 2(4)

8 Cholesterol-lowering drugs and Alzheimer s disease REVIEW Executive summary Cholesterol & Alzheimer s disease (AD): in vitro & in vivo studies Cell culture studies show that statin induced changes of membrane cholesterol controls the direction of the processing of the amyloid-precursor protein (APP) in vitro. Studies on synaptosomal plasma membranes demonstrated that statins induce discrete changes in cholesterol microdomains within the membrane, such as transbilayer distribution and lipid rafts. Cholesterol levels in humans Data supporting elevated serum, CSF or brain cholesterol levels as a risk factor in AD have not been consistently observed. There may be important changes in cholesterol homeostasis in AD patients, but such proposed changes are occurring in cholesterol domains in contrast to changes in bulk cholesterol levels. Statins in clinical studies Epidemiological trials indicate that statins significantly decreased the incidence of AD. Meta-analysis of prospective studies concluded that a more than a modest role for statins in preventing AD appears unlikely. Conclusion Long-term prevention data look promising. Efficacy of statins, whether in prevention or treatment of AD, is not proven due to inconsistent findings. Future perspective The potential efficacy of statins in neuroprotection may be unrelated to cholesterol biosynthesis. Hence, discovering how statins are stimulating anti-apoptotic genes will offer new insight into the potential use of other cholesterol-lowering and lipid-related drugs that might have neuroprotective efficacy Bibliography Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Hamelin BA, Turgeon J: Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci. 19, (1998). 2. Lousberg TR, Denham AM, Rasmussen JR: A comparison of clinical outcome studies among cholesterol-lowering agents. Ann. Pharmacother. 35(12), (2001). 3. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F: New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol. Ther. 84(3), (1999). Good overview of the pharmacodynamics and pharmokinetics of statins. 4. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F: Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc. Natl Acad. Sci. USA 98(10), (2001). 5. Schachter M: Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam. Clin. Pharmacol. 19(1), (2005). 6. Neuvonen PJ, Niemi M, Backman JT: Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin. Pharmacol. Ther. 80(6), (2006). 7. Botti RE, Triscari J, Pan HY, Zayat J: Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin. Neuropharmacol. 14(3), (1991). 8. Johnson-Anuna LN, Eckert GP, Keller JH et al.: Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J. Pharmacol. Exp. Ther. 312(2), (2005). Expression of genes involved in apoptosis, glucose homeostasis, neuronal growth, cell motility and differentiation are regulated by statins. 9. Thelen KM, Rentsch KM, Gutteck U et al.: Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin. J. Pharmacol. Exp. Ther. 316(3), (2005). 10. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA: Molecular pathways to neurodegeneration. Nat. Med. 10(Suppl.), S2 S9 (2004). 11. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer s disease: progress and problems on the road to therapeutics. Science 297(5580), (2002). 12. Michikawa M: The role of cholesterol in pathogenesis of Alzheimer s disease: dual metabolic interaction between amyloid betaprotein and cholesterol. Mol. Neurobiol. 27(1), 1 12 (2003). 13. Wood WG, Eckert GP, Igbavboa U, Müller WE: Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer s disease. Biochim. Biophys. Acta 1610(2), (2003). 14. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM: The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10(8), (1999). 15. Bodovitz S, Klein WL: Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 271(8), (1996). 16. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K: Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc. Natl Acad. Sci. USA 95(11), (1998). 17. Fassbender K, Simons M, Bergmann C et al.: Simvastatin strongly reduces levels of Alzheimer s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl Acad. Sci. USA 98(10), (2001)

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11 REVIEW Eckert, Müller & Wood 86. Mcfarlane SI, Muniyappa R, Francisco R, Sowers JR: Pleiotropic effects of statins: Lipid reduction and beyond. J. Clin. Endocrinol. Metab. 87, (2002). 87. Cole SL, Grudzien A, Manhart I, Kelly B, Oakley H, Vassar R: A tale of two statins: the effects of lovastatin and simvastatin on APP metabolism. Neurobiol. Aging 25(S2), 77 (2004). 88. Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME Gandy S: Modulation of statin-activated shedding of alzheimer APP ectodomain by ROCK. PLoS. Med. 2(1), e18 (2005). 89. Johnson-Anuna LN, Eckert GP, Franke C, Igbavboa U, Muller WE, Wood WG: Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mrna and protein. J. Neurochem. 101(1), (2007). 90. Franke C, Nöldner M, Abdel-Kader R et al.: Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment. Neurobiol. Dis. 25(2), (2007). Simvastatin exerts neurotropic effects, which are presumably out of the mevalonate pathway and involve the regulation of apoptosis. Affiliations Gunter P Eckert University of Frankfurt, Department of Pharmacology, Biocenter Niederursel, Mari-Curie-Str. 9, D Frankfurt, Germany Tel.: ; Fax: ; g.p.eckert@em.uni-frankfurt.de Walter E Müller University of Frankfurt, Department of Pharmacology, Biocenter Niederursel, Mari-Curie-Str. 9, D Frankfurt, Germany Tel.: ; Fax: ; pharmacolnat@em.uni-frankfurt.de W Gibson Wood University of Minnesota School of Medicine and Geriatric Research, Department of Pharmacology, Education and Clinical Center, VA Medical Center, Minneapolis, MN 55417, USA Tel.: ; Fax: ; woodx002@emn.edu 432 Future Lipidol. (2007) 2(4)