Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

Butterfield, D. Allan; Barone, Eugenio; Mancuso, Cesare

doi:10.1016/j.phrs.2011.04.007

Cited by 80Alzheimer's disease research and treatmentsLipoproteins and Cardiovascular HealthCancer, Lipids, and Metabolism

Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

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Butterfield, D. Allan, Barone, Eugenio, Mancuso, Cesare·2011·Pharmacological Research

DOI 10.1016/j.phrs.2011.04.007PMC PMC3130102

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Abstract

Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects in preclinical studies and lack effectiveness in various recent clinical trials. This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with particular emphasis on Alzheimer disease.

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Atorvastatin and many other statins cross the blood-brain barrier poorly, yet atorvastatin use is linked to lower AD risk.
“Many statins, including atorvastatin, do not penetrate the blood-brain barrier (BBB) significantly, yet atorvastatin use is associated with lowered risk of developing AD113,114.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [113]
Section 3, “Statins and dementia” (page unavailable), reports that early observational studies linked statin use with reduced risk of developing dementia, including AD, but does not identify atorvastatin specifically for that association. Its “Ability to cross membranes” subsection describes atorvastatin as having intermediate lipophilicity and discusses how that may affect the fraction reaching the brain; it does not say that atorvastatin or many other statins cross the BBB poorly. (LLM, conf=0.83)
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Result
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BackgroundSelf-citation
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Method
Pitavastatin
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Result
Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment
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Result
Cholesterol and statins in Alzheimer's disease: Current controversies
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Background
Age‐Varying Association Between Statin Use and Incident Alzheimer's Disease
Li, G., Shofer, J. B., Rhew, I. C., Kukull, W. A., Peskind, E. R., McCormick, W. C., Bowen, J. D., Schellenberg, G. D., Crane, P. K., Breitner, J. C. S., et al. (2010) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2010.02906.x · Cited by 111 · cited 2× · see citing works
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BackgroundResult
Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid
Riekse, R. G., Li, G., Petrie, E. C., Leverenz, J. B., Vavrek, D. A., Vuletic, S., Albers, J. J., Montine, T. J., Lee, V. M. ‐., Lee, M., et al. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-10408 · Cited by 110 · cited 1× · see citing works
“Statins showed positive effects against Alzheimer-relevant Aβ-induced oxidative stress in mice models of AD [41,42] as well as a reduction in CSF tau protein phosphorylation in humans [43].”
Background
Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol
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Background
Statin therapy in Alzheimer's disease
Sparks, D. L., Sabbagh, M., Connor, D. J., Soares, H. D., Lopez, J., Stankovic, G. R., Johnson‐Traver, S., Ziolkowski, C. H. J., & Browne, P. J. (2006) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2006.00689.x · Cited by 104 · cited 1× · see citing works
“However, this beneficial effect was narrowed to individuals who matched restricted criteria, such as a higher MMSE score at the baseline, total cholesterol levels higher than 200 mg/dl and the presence of an apolipoprotein-E-4 allele [75,76].”
Background
Plasma Levels of β-Amyloid(1-40), β-Amyloid(1-42), and Total β-Amyloid Remain Unaffected in Adult Patients With Hypercholesterolemia After Treatment With Statins
Höglund, K., Wiklund, O., Vanderstichele, H., Eikenberg, O., Vanmechelen, E., & Blennow, K. (2004) · Archives of Neurology · doi:10.1001/archneur.61.3.333 · Cited by 102 · cited 1× · see citing works
“clearance [43,86].”
Statins and Cognitive Functioning in the Elderly: A Population-Based Study
Benito‐León, J., Louis, E. D., Vega, S., & Bermejo‐Pareja, F. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100180 · Cited by 97 · cited 1× · see citing works
“, who demonstrated that statins did not improve cognition in elderly subjects with a median age of 72 years [68].”
Background
Blockade of HMG‐CoA reductase activity causes changes in microtubule‐stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease
Meske, V., Albert, F., Richter, D., Schwarze, J., & Ohm, T. G. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02433.x · Cited by 94 · cited 1× · see citing works
“In contrast, the same drugs efficiently inhibited Ras-induced ERK1/2 phospshorylation in rat brain neuroblasts [20], as well as geranylgeranylation of Rho family GTPase in neurons [21], leading to an increase in apotosis and tau phosphorylation, respectively [20,21] (Figure 1).”
Background
Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: A novel mechanism of action
Barone, E., Cenini, G., Domenico, F. D., Martin, S. K., Rukhsana Sultana, A., Mancuso, C., Murphy, M. P., Head, E., & Butterfield, D. A. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.12.007 · Cited by 92 · cited 4× · see citing works
“This recommendation could be especially important since preclinical studies with atorvastatin decreased brain-resident oxidative stress in beagle dogs, and this benefit was correlated with decreased levels of Aβ(1–42), which has the same sequence as that of humans [46].”
BackgroundInfluentialSelf-citation
Statins for the treatment of dementia
McGuinness, B., O’Hare, J., Craig, D., Bullock, R. A., Malouf, R. S., & Passmore, P. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007514.pub2 · Cited by 92 · see citing works
Simvastatin regulates oligodendroglial process dynamics and survival
Miron, V. E., Rajasekharan, S., Jarjour, A. A., Zamvil, S. S., Kennedy, T. E., & Antel, J. P. (2006) · Glia · doi:10.1002/glia.20441 · Cited by 91 · cited 1× · see citing works
“Conversely, prolonged treatment of human mature oligodentrocyte with simvastatin was associated with cell death [17] (Figure 1).”
Background
Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: Reduction during atorvastatin and fenofibrate therapy
Arca, M., Natoli, S., Micheletta, F., Riggi, S., Angelantonio, E. D., Montali, A., Antonini, T., Antonini, R., Diczfalusy, U., & Iuliano, L. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.12.013 · Cited by 86 · cited 1× · see citing works
“Although some evidence suggests the importance of cholesterol oxidation products both as in vivo markers of oxidative stress [54–56], as well as for their pro-oxidant features [51– 53,57], few studies exist regarding the effect of statins on cholesterol oxidation products in vivo [54,58,59].”
Background
In vivo interconversion of 7β-hydroxycholesterol and 7-ketocholesterol, potential surrogate markers for oxidative stress
Larsson, H., Böttiger, Y., Iuliano, L., & Diczfalusy, U. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.04.033 · Cited by 84 · see citing works
Statin-associated rhabdomyolysis triggered by grapefruit consumption
Dreier, J. P., & Endres, M. (2004) · Neurology · doi:10.1212/wnl.62.4.670 · Cited by 81 · see citing works
Inhibition of Rho Family Functions by Lovastatin Promotes Myelin Repair in Ameliorating Experimental Autoimmune Encephalomyelitis
Paintlia, A. S., Paintlia, M. K., Singh, A. K., & Singh, I. (2008) · Molecular Pharmacology · doi:10.1124/mol.107.044230 · Cited by 73 · cited 1× · see citing works
“Lovastatin, was effective to ameliorate experimental autoimmune encephalomyelitis by reducing the activities of Rho/Ras family GTPase in glial cells [19].”
Background
Treatment of statin adverse effects with supplemental Coenzyme Q10 and statin drug discontinuation
Langsjoen, P. H., Langsjoen, J., Langsjoen, A. M., & Lucas, L. A. (2005) · BioFactors · doi:10.1002/biof.5520250116 · Cited by 73 · cited 1× · see citing works
“Supplementation of the diet with CoQ10 was reported to reverse many of these alterations [48].”
Background
A Rho-associated Protein Kinase, ROKα, Binds Insulin Receptor Substrate-1 and Modulates Insulin Signaling
Farah, S., Agazie, Y. M., Ohan, N. W., Ngsee, J. K., & Liu, X. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.8.4740 · Cited by 70 · cited 1× · see citing works
“Downstream consequences of reduced isoprenoid synthesis may include changes in vascular function, modulation of the insulin/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway [24] and possibly a reduction in reactive oxygen species production [25].”
Background
Isoprenoids and Alzheimer's disease: A complex relationship
Cole, S. L., & Vassar, R. J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.11.007 · Cited by 70 · cited 1× · see citing works
“Through the inhibition of HMG-CoA reductase activity, statins reduce the formation of L-mevalonic acid and subsequent prevention of isoprenoid synthesis [4,7,8].”
Background
Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging
Reiman, E. M., Chen, K., Langbaum, J. B. S., Lee, W., Reschke, C., Bandy, D. J., Alexander, G. E., & Caselli, R. J. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.07.025 · Cited by 70 · see citing works
Statins in the treatment of central nervous system autoimmune disease
Weber, M. S., Youssef, S., Dunn, S. E., Prod’homme, T., Neuhaus, O., Stüve, O., Greenwood, J., Steinman, L., & Zamvil, S. S. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.06.006 · Cited by 67 · cited 1× · see citing works
“Although initially statins were thought to be beneficial for myelination and proposed as a treatment for multiple sclerosis (MS), a demyelinating condition [26,27], these benefits are being re-evaluated, since contradictory results have been described.”
Result
The cholesterol-lowering drug Probucol increases apolipoprotein e production in the hippocampus of aged rats: implications for Alzheimer’s disease
Champagne, D. L., Pearson, D., Dea, D., Rochford, J. M., & Poirier, J. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00361-0 · Cited by 66 · cited 1× · see citing works
“In vitro, lovastatin prevents expression of TNF and IL-1β [33], and prubocol reduces glial activation [34].”
Background
25‐hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase A2 type IIA via LXR beta and PXR
Trousson, A., Bernard, S., PETIT, P. X., Lière, P., Pianos, A., Hadri, K. E., Lobaccaro, J. A., Ghandour, M. S., Raymondjean, M., Schumacher, M., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06009.x · Cited by 64 · cited 1× · see citing works
“Among oxysterols, 7-ketocholesterol (7-K) and 25hydroxycholesterol (25-OH) have been shown to cause apoptotic neuronal death by inducing mitochondrial dysfunction [51], Ca2+ influx and perturbation of intracellular ionic homeostasis [52,53].”
Background
Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis
Paintlia, A. S., Paintlia, M. K., Singh, I., Skoff, R. B., & Singh, A. K. (2008) · Glia · doi:10.1002/glia.20745 · Cited by 58 · cited 1× · see citing works
“Although initially statins were thought to be beneficial for myelination and proposed as a treatment for multiple sclerosis (MS), a demyelinating condition [26,27], these benefits are being re-evaluated, since contradictory results have been described.”
Result
Influence of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors on endothelial nitric oxide synthase and the formation of oxidants in the vasculature
Parker, R. A. (2003) · Atherosclerosis · doi:10.1016/s0021-9150(03)00100-x · Cited by 56 · see citing works
Gas chromatography–mass spectrometry-based simultaneous quantitative analytical method for urinary oxysterols and bile acids in rats
Kumar, B. S., Chung, B. C., Lee, Y. J., Yi, H. J., Lee, B., & Jung, B. H. (2010) · Analytical Biochemistry · doi:10.1016/j.ab.2010.09.031 · Cited by 54 · see citing works
Effects of statins on microglia
Lindberg, C., Crisby, M., Winblad, B. G., & Schultzberg, M. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20615 · Cited by 53 · cited 1× · see citing works
“In addition, microglial cultures exposed to atorvastatin and simvastatin showed reduced levels of the pro-inflammatory cytokine, IL-6 [35] (Figure 1).”
Background
High‐Dose Statin Treatment Does Not Alter Plasma Marker for Brain Cholesterol Metabolism in Patients With Moderately Elevated Plasma Cholesterol Levels
Thelen, K., Laaksonen, R., Päivä, H., Lehtimäki, T. J., & Lütjohann, D. (2006) · The Journal of Clinical Pharmacology · doi:10.1177/0091270006289851 · Cited by 52 · cited 1× · see citing works
“Although some evidence suggests the importance of cholesterol oxidation products both as in vivo markers of oxidative stress [54–56], as well as for their pro-oxidant features [51– 53,57], few studies exist regarding the effect of statins on cholesterol oxidation products in vivo [54,58,59].”
Background
Cholesterol and Cognitive Performance in Normal Controls and the Influence of Elective Statin Use after Conversion to Mild Cognitive Impairment: Results in a Clinical Trial Cohort
Sparks, D. L., Kryscio, R. J., Connor, D. J., Sabbagh, M. N., Sparks, L. M., Lin, Y., & Liebsack, C. (2010) · Neurodegenerative Diseases · doi:10.1159/000295660 · Cited by 48 · cited 1× · see citing works
“Only a weak improvement in cognitive performance (evaluated by the Hopkins word list and Rivermead paragraph) was found in individuals with mild cognitive impairment, arguably the earliest form of AD, treated with statins [70].”
ras isoprenylation is required for ras-induced but not for NGF-induced neuronal differentiation of PC12 cells.
Qiu, M., Pitts, A. F., Winters, T. R., & Green, S. H. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.115.3.795 · Cited by 46 · cited 1× · see citing works
“Moreover, mevastatin and lovastatin were reported to, respectively, decrease and increase neurite outgrowth in different strains of PC12 cells through different mechanisms [22,23].”
Background
Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts
Cerezo-Guisado, M. I., Garcı́a-Román, N., Garcı́a, L. J., Alvarez, A. M., Bragado, M. J., & Lorenzo, M. J. V. (2006) · Biochemical Journal · doi:10.1042/bj20060731 · Cited by 44 · cited 1× · see citing works
“In contrast, the same drugs efficiently inhibited Ras-induced ERK1/2 phospshorylation in rat brain neuroblasts [20], as well as geranylgeranylation of Rho family GTPase in neurons [21], leading to an increase in apotosis and tau phosphorylation, respectively [20,21] (Figure 1).”
Background
Prevention of amyloid β-induced memory impairment by fluvastatin, associated with the decrease in amyloid β accumulation and oxidative stressin amyloid β injection mouse model
Kurinami, H., Sato, N., Shinohara, M., Takeuchi, D., Takeda, S., Shimamura, M., Ogihara, T., & Morishita, R. (2008) · International Journal of Molecular Medicine · doi:10.3892/ijmm.21.5.531 · Cited by 43 · see citing works
Lovastatin induces the formation of abnormal myelin‐like membrane sheets in primary oligodendrocytes
Maier, O., Jonge, J. D., Nomden, A., Hoekstra, D., & Baron, W. (2008) · Glia · doi:10.1002/glia.20769 · Cited by 43 · cited 1× · see citing works
“Interestingly, simvastatin and lovastatin had an opposite effect on the myelin basic protein (MBP), since simvastatin treatment greatly increased the densities of MBP in oligodentrocytes of neonatal rats after hypoxia-ischemia damage [30], whereas lovastatin reduced MBP expression in primary oligodentrocytes, probably…”
Background
P3‐391: Statins for the treatment of dementia
McGuinness, B., O’Hare, J., Bullock, R. A., Malouf, R. S., Craig, D., & Passmore, P. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.05.1933 · Cited by 40 · cited 3× · see citing works
“However, although there was beneficial effect of statins on LDLcholesterol plasma levels, no beneficial effect on cognitive function was observed [77,85].”
Background
The Effect of Green Tea on Simvastatin Tolerability
Werba, J. P., Giroli, M., Cavalca, V., Nava, M. C., Tremoli, E., & Bo, L. D. (2008) · Annals of Internal Medicine · doi:10.7326/0003-4819-149-4-200808190-00019 · Cited by 39 · cited 1× · see citing works
“Interestingly, it was reported that the concomitant assumption of simvastatin and grapefruit or green tea originated rhabdomyolisis [92,93].”
Background
Changes in Cognition and Amyloid-β Processing with Long Term Cholesterol Reduction using Atorvastatin in Aged Dogs
Murphy, M. P., Morales, J., Beckett, T. L., Astarita, G., Piomelli, D., Weidner, A. M., Studzinski, C. M., Dowling, A. L. S., Wang, X., LeVine, H., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100639 · Cited by 38 · cited 2× · see citing works
“Murphy et al. (2010) showed that long-term atorvastatin did not affect Aβ levels, despite a significant reduction in β-secretase 1 (BACE1) protein levels and activity in the brain of aged beagles [45].”
Background
Prevention of 7-ketocholesterol-induced mitochondrial damage and cell death by calmodulin inhibition
Han, J. H., Kim, Y. J., Han, E. S., & Lee, C. S. (2006) · Brain Research · doi:10.1016/j.brainres.2006.12.041 · Cited by 37 · cited 1× · see citing works
“Among oxysterols, 7-ketocholesterol (7-K) and 25hydroxycholesterol (25-OH) have been shown to cause apoptotic neuronal death by inducing mitochondrial dysfunction [51], Ca2+ influx and perturbation of intracellular ionic homeostasis [52,53].”
Background
Long-Term Statin Therapy and CSF Cholesterol Levels: Implications for Alzheimer’s Disease
Evans, B. A., Evans, J. E., Baker, S. P., Kane, K., Swearer, J. M., Hinerfeld, D. A., Caselli, R. J., Rogaeva, E. A., George‐Hyslop, P. S., Moonis, M., et al. (2009) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000221835 · Cited by 31 · cited 1× · see citing works
“showed that in AD patients heterozygous for APOE4 allele or carriers of PS1 mutations, the administration of simvastatin or atorvastatin slightly reduced the concentration of CSF-cholesterol at 6–7 months followed by a peak at 2 years and a return to baseline levels after three years [87].”
Background
Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination
Xiang, Z., & Reeves, S. A. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.09.010 · Cited by 31 · cited 1× · see citing works
“Simvastatin treatment had a detrimental effect on oligodentrocyte outgrowth, a key step in the re(myelination) process [28], particularly in the early myelination stage [29] (Figure 1).”
Background
Statins in the spectrum of neurologic disease
Orr, J. D. (2008) · Current Atherosclerosis Reports · doi:10.1007/s11883-008-0003-5 · Cited by 27 · cited 1× · see citing works
“Another intriguing aspect related to the pleiotropic effects induced by statin treatment regards the modulation of oxidative stress-related modifications that occur in neurodegenerative disorders [36].”
Background
Exploring new indications for statins beyond atherosclerosis: Successes and setbacks
Waters, D. D. (2010) · Journal of Cardiology · doi:10.1016/j.jjcc.2009.12.003 · Cited by 27 · cited 2× · see citing works
“In 2008 the CLASP study was designed to evaluate the neuroprotective role of simvastatin (20–40 mg/day) for 18 months in mild-moderate AD patients [74].”
Background
Simvastatin attenuates hypomyelination induced by hypoxia–ischemia in neonatal rats
Li, A., Lv, S., Yu, Z., Zhang, Y., Ma, H., Zhao, H., Piao, H. Z., Li, S., Zhang, N., & Sun, C. (2010) · Neurological Research · doi:10.1179/016164110x12670144737774 · Cited by 27 · cited 1× · see citing works
“Interestingly, simvastatin and lovastatin had an opposite effect on the myelin basic protein (MBP), since simvastatin treatment greatly increased the densities of MBP in oligodentrocytes of neonatal rats after hypoxia-ischemia damage [30], whereas lovastatin reduced MBP expression in primary oligodentrocytes, probably…”
Background
Use of Statins and Risk of Hospitalization With Dementia
Horsdal, H. T., Olesen, A. V., Gasse, C., Sørensen, H. T., Green, R. C., & Johnsen, S. P. (2009) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318180f55b · Cited by 24 · cited 1× · see citing works
“Early clinical data based on cohort and case-control studies, demonstrated that statins reduced the risk to develop dementia, including Alzheimer disease (AD), and this protective effect was maintained over a 6 year follow-up period [60–67].”
Result
Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: Synergism with a ROCK inhibitor but not the thrombolytic tissue plasminogen activator
Lapchak, P. A., & Han, M. (2010) · Brain Research · doi:10.1016/j.brainres.2010.05.035 · Cited by 24 · cited 1× · see citing works
“Neuroprotective effects of simvastatin for example, include the improvement of behavioral function associated with an inhibition of Rho-associated kinase (ROCK) in a rabbit model of ischemic stroke [15], and the prevention of dopaminergic neuronal loss trough the inhibition of p21(ras)-induced NF-kappaB increase in a…”
Background
Grapefruit juice and potential drug interactions.
Hare, J. T., & Elliott, D. P. (2003) · PubMed · Cited by 24 · see citing works
Equivalent lipid oxidation profiles in advanced atherosclerotic lesions of carotid endarterectomy plaques obtained from symptomatic type 2 diabetic and nondiabetic subjects
Kathir, K., Dennis, J. M., Croft, K. D., Mori, T. A., Lau, A. K., Adams, M. R., & Stocker, R. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.05.006 · Cited by 20 · cited 1× · see citing works
“Although some evidence suggests the importance of cholesterol oxidation products both as in vivo markers of oxidative stress [54–56], as well as for their pro-oxidant features [51– 53,57], few studies exist regarding the effect of statins on cholesterol oxidation products in vivo [54,58,59].”
Background
Simvastatin interferes with process outgrowth and branching of oligodendrocytes
Smolders, I., Smets, I., Maier, O., vandeVen, M., Steels, P., & Ameloot, M. M. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22490 · Cited by 20 · cited 1× · see citing works
“Simvastatin treatment had a detrimental effect on oligodentrocyte outgrowth, a key step in the re(myelination) process [28], particularly in the early myelination stage [29] (Figure 1).”
Background
Management of grapefruit-drug interactions.
Stump, A. L., Mayo, T., & Blum, A. (2006) · PubMed · Cited by 20 · see citing works
Localization of G alpha 0 to growth cones in PC12 cells: role of G alpha 0 association with receptors and G beta gamma.
Nüsse, O., & Neer, E. J. (1996) · PubMed · doi:10.1242/jcs.109.1.221 · Cited by 19 · see citing works
Erratum
(2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111438 · Cited by 13 · see citing works
Women and statin use: A women's health advocacy perspective
Rosenberg, H. G., & Allard, D. (2008) · Scandinavian Cardiovascular Journal · doi:10.1080/14017430801993180 · Cited by 11 · cited 1× · see citing works
“Early clinical data based on cohort and case-control studies, demonstrated that statins reduced the risk to develop dementia, including Alzheimer disease (AD), and this protective effect was maintained over a 6 year follow-up period [60–67].”
Result
Atorvastatin and Aβ(1–40): Not as Simple as Cholesterol Reduction in Brain and Relevance to Alzheimer Disease
Butterfield, D. A. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.12.014 · Cited by 9 · cited 1× · see citing works
“However, although statin treatment appears to provide greater benefits, it is difficult to tease out whether the benefits are really due to lower cholesterol levels or to statin pleiotropy [6].”
BackgroundSelf-citation

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Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954 · see citing works
Self-citation
Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors
Tayeb, H. O., Yang, H. D., Price, B. H., & Tarazi, F. I. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.12.002 · Cited by 231 · see citing works
Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases
Song, K., Li, Y., Zhang, H., An, N., Wei, Y., Wang, L., Tian, C., Yuan, M., Sun, Y., Xing, Y., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/4356386 · Cited by 199 · see citing works
“, statins), which has antioxidant and neuroprotective functions that could be of great advantage in neurological diseases [106, 107].”
Background
Blood-Brain Barrier Integrity and Glial Support: Mechanisms that can be Targeted for Novel Therapeutic Approaches in Stroke
Ronaldson, P. T., & Davis, T. P. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802002625 · Cited by 157 · see citing works
Cholesterol metabolism in Huntington disease
Karasinska, J. M., & Hayden, M. R. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.132 · Cited by 154 · see citing works
Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases
Dattilo, S., Mancuso, C., Koverech, G., Mauro, P. D., Ontario, M. L., Petralia, C. C. T., Petralia, A., Maiolino, L., Serra, A., Calabrese, E. J., et al. (2015) · Immunity & Ageing · doi:10.1186/s12979-015-0046-8 · Cited by 140 · see citing works
“Taken together, these results demonstrate that the HO1/BVR axis can be modulated by atorvastatin and open new avenues in terms of activation of the HO-1/BVR system and neuroprotection [80, 81].”
BackgroundSelf-citation
Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”
Cornelius, C., Perrotta, R. E., Graziano, A., Calabrese, E. J., & Calabrese, V. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-15 · Cited by 131 · see citing works
“Within this context, heme-derived free ferrous iron, CO, and biliverdin/ bilirubin are all biologically active substances that can either ameliorate or exacerbate neural injury contingently to the specific disease conditions, such as intensity and duration of HO-1 expression and/or the nature of the resulting redox mi…”
Background
The 2013 SFRBM Discovery Award: Selected discoveries from the Butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment
Butterfield, D. A. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.06.006 · Cited by 126 · see citing works
“All these functions are lost in AD and aMCI, demonstrating again that redox proteomics-identified proteins often mirror the pathology and clinical presentation of this disease.”
BackgroundInfluentialSelf-citation
Cholesterol and Late-Life Cognitive Decline
van Vliet, P. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111028 · Cited by 122 · see citing works
Modulatory Role of Simvastatin against Aluminium Chloride-Induced Behavioural and Biochemical Changes in Rats
Nampoothiri, M., John, J., Kumar, N., Mudgal, J., Nampurath, G. K., & Chamallamudi, M. R. (2015) · Behavioural Neurology · doi:10.1155/2015/210169 · Cited by 105 · see citing works
Lipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors
Kang, J., & Rivest, S. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1049 · Cited by 94 · see citing works
Simvastatin and atorvastatin facilitates amyloid β‐protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/E rk1/2 pathways
Yamamoto, N., Fujii, Y., Kasahara, R., Tanida, M., Ohora, K., Ono, Y., Suzuki, K., & Sobue, K. (2016) · Glia · doi:10.1002/glia.22974 · Cited by 80 · see citing works
“Isoprenoid is thought to contribute substantially to cell- and tissue-specific anti-inflammatory and immunomodulatory effects of statin activity (Butterfield et al., 2011; Cordy et al., 2006; Jasi nska et al., 2007; Parsons et al., 2007).”
Statins more than cholesterol lowering agents in Alzheimer disease: Their pleiotropic functions as potential therapeutic targets
Barone, E., Domenico, F. D., & Butterfield, D. A. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.10.030 · Cited by 79 · see citing works
“Our group was the first to propose BVR-A as a novel drug-target for atorvastatin in the brain [7,143].”
BackgroundInfluentialSelf-citation
Biliverdin reductase‐A: a novel drug target for atorvastatin in a dog pre‐clinical model of Alzheimer disease
Barone, E., Mancuso, C., Di Domenico, F., Sultana, R., Murphy, M. P., Head, E., & Butterfield, D. A. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07538.x · Cited by 75 · see citing works
“However, the importance of statin treatment in AD is still under debate, given that some randomized clinical trials did not show any significant benefit on cognition as reviewed by (McGuinness et al. 2010; Butterfield et al. 2011a).”
BackgroundInfluentialSelf-citation
Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer’s disease (AD)
Lukiw, W. J. (2012) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.2012.672559 · Cited by 74 · see citing works
“In addition, statins are of effective use in hypercholesterolemia, hyperlipidemic cardiovascular and neurovascular diseases, common disorders known to be contributory to for the development of AD [96-98,91,127,140,118].”
Background
Apolipoprotein A ‐ I : Insights from redox proteomics for its role in neurodegeneration
Keeney, J. T. R., Swomley, A. M., Förster, S., Harris, J. L., Rukhsana Sultana, A., & Butterfield, D. A. (2012) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201200087 · Cited by 73 · see citing works
Self-citation
Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury
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Additional file 2 of DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice
Zhang, W.-B., Huang, Y., Guo, X.-R., Zhang, M.-Q., 袁向山, & Zu, H.-B. (2024) · Figshare · doi:10.6084/m9.figshare.26598869
Additional file 1 of DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice
Zhang, W.-B., Huang, Y., Guo, X.-R., Zhang, M.-Q., 袁向山, & Zu, H.-B. (2024) · Figshare · doi:10.6084/m9.figshare.26598866
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Authors: Butterfield, D. A., Barone, E., & Mancuso, C.
Affiliations: University of Kentucky (US)
Università Cattolica del Sacro Cuore (IT)
Corresponding author: Butterfield, D. Allan
ORCID: Butterfield, D. Allan
Barone, Eugenio
Mancuso, Cesare
Venue: Pharmacological Research
Publisher: Elsevier BV
Published: 2011-09
Volume: 64
Issue: 3
Pages: 180-186
ISSN: 1043-6618 (ISSN-L)
DOI: 10.1016/j.phrs.2011.04.007
PMC: PMC3130102
OpenAlex: W2157524121
Cited by: 80
References: 105
Citations by year: 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 6 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 10 · 2015: 11 · 2014: 3 · 2013: 7 · 2012: 8
FWCI: 4.58
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacological Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders: NIH (AG-05119)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: statins, Alzheimer's disease, neurodegenerative diseases, cholesterol-independent effects, neuroprotection, neurotoxicity, pleiotropy, age-related neurodegeneration, cholesterol lowering, dyslipidemia, clinical trials
MeSH terms: Rosuvastatin Calcium, Atorvastatin, Fluvastatin, Alzheimer Disease, Animals, Cholesterol, Fatty Acids, Monounsaturated, Fluorobenzenes, Heptanoic Acids, Humans, Indoles, Lovastatin, Pyrimidines, Pyrroles, Quinolines, Sulfonamides, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Neurodegenerative Diseases

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Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

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