N. Yan et al. /Aging and Neurodegeneration, Vol. 1 (1): 20-24, September 2013
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Review Article
Statins are Protective Against Beta-amyloid
Pathology in Alzheimer's Disease ?
Ning Yan1, Yong Yan2, Zhiyou Cai3*

Abstract: An increasing number of studies have supported that
high cholesterol is a risk factor for the pathogenesis of
Alzheimer's disease ( AD ), including beta-amyloid peptides ( Aβ )
pathology. Clinical and biomolecular research studies have
accumulated that statins, cholesterol-lowering drugs, could stave
off the symptoms of AD and have seemed one of the most
promising drugs in the war against AD. The role of cholesterol in
the process of Aβ production and deposition has been fully
considered on the basis of scientific results during the last 2
decades. It is clear that statins play a neuroprotective role in
limiting A pathology via cholesterol-lowering therapies. In
addition, statins may favor the α-secretase nonamyloidogenic
pathway of APP processing and inhibit the dimerization of
-secretase. According to non-lipid property of statins, statins
retard Aβ pathology via its anti-inflammation, anti-atherosclerotic
actions, anti-oxidant and anti-apoptosis. However, compelling
studies available indicate that statins have no benefit on AD and
do not help prevent AD. Regarding statins as preventive
medicines, there are a number of individual clinical cases where
cognition is clearly and reproducibly adversely affected by statins.
Statins have a range of mechanisms that could help or hurt
cognition? In spite of limiting A pathology, several evidence
reported that statins enhanced the development of A pathology.
Statin medications were further harmful to Aβ pathology? It
appears that there is still a lot of work to implement statin
medications in clinical and preclinical studies of AD.
Keywords: Alzheimer's disease, beta-amyloid peptides, statin
1. Introduction
A
LZHEIMER’S disease (AD) is a progressive, degenerative
disorder that attacks the brain's nerve cells, or neurons,
resulting in loss of memory, thinking and language skills, and
behavioral changes[1, 2]. The two pathological hallmarks of AD
include beta-amyloid (Aβ) plaques (extracellular Aβ deposition)
and neurofibrillary tangles (NFTs, intracellular deposits of
hyper-phosphorylated tau protein) [3, 4]. AD pathogenesis is
widely believed to be driven by the production and deposition of
the Aβ [5, 6]. Accordingly, mounting studies have focused on the
research of Aβ generation and deposition to discover the role in
the process of AD [7, 8].
1
Neuroscience Center, the University-City’s Affiliated Hospital of Chongqing
Medical University, Chongqing, China, 401331
2
Department of Neurology, the first affiliated hospital of Chongqing Medical
University , Number 1 Youyi Road, Chongqing, China, 400016
3
Department of Neurology, the Lu’an Affiliated Hospital of Anhui Medical
University, Lu’an People’s Hospital, Lu’an, Anhui Province, 237005, China
*Correspondence to Zhiyou Cai ( e-mail: c0909@hotmail.com ).
(Received July 28, 2013; Revised August 23, 2013; Accepted August 30, 2013)
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The statins, HMG-CoA reductase inhibitors, are a class of drugs
that lower blood cholesterol levels [9-11]. It is well known that
increased cholesterol levels have been associated with many
disorders, including cardiovascular diseases [12-16] and
neurodegenerative diseases [17-19]. The value of statins not only
has been clearly established in preventing heart disease, but will
benefit the inhibition of neurodegenerative pathology as well. A
variety of research data has indicated that statins are protective
against the development of AD [17, 20, 21], suggesting that statins
improve cognitive impairment and restrain beta-amyloid plaques
and neurofibrillary tangles via several biomolecular mechanisms
(anti-oxidant, anti-inflammation, anti-atherosclerotic progress,
anti-apoptosis, and so on ) ( Figure 1 ).
This work reviewed the role of statins in Aβ pathology. The
proposed neuroprotective mechanisms of statins were provided in
Aβ pathology mainly via increased -secretase activity and
decreased -secretase and γ-secretase activity and non-lipid
effects such as anti-inflammation, anti-atherosclerotic actions,
anti-oxidant and anti-apoptosis. Finally, we also looked into the
future whether statins are possibly a class of agents as an attractive
target for AD prevention and treatment.
2. Statins
Statins (or HMG-CoA reductase inhibitors) are a class of drugs
including Lipitor (an atorvastatin), Crestor (a rosuvastatin), Zocor
(a simvastatin), Pravachol (a pravastatin), Lescol (a fluvastatin),
Vytorin ( simvastatin and ezetimibe) and mevastatin. The basic
function of statins is to lower cholesterol levels by inhibiting the
enzyme HMG-CoA reductase [22]. The main mechanism is that
statins lower cholesterol levels by increasing LDL receptors
activity and taking cholesterol from the blood, decreasing
cholesterol synthesis in liver and free cholesterol concentration
[23]. Increasing scientific studies have demonstrated that
increased cholesterol levels have been associated with various
diseases such as cardiovascular disease (CVD) [24, 25], metabolic
syndrome [26, 27], obesity [26], diabetes [26, 28, 29], as well as
neurodegenerative diseases [19, 30]. A wide variety of research
data has found not only that statins are effective for treating CVD
as a secondary prevention strategy [16, 31], metabolic syndrome
[32, 33], obesity [24] and diabetes [34, 35], but also statins may be
effective neuroprotective agents such as cerebral ischemia and
neurodegenerative diseases [21, 22, 30, 36].
3. Dyslipidemia, Statins and Alzheimer's
Increasing data from basic studies and clinical research shows that
hypercholesterolemia is a significant risk factor in the
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N. Yan et al. /Aging and Neurodegeneration, Vol. 1 (1): 20-24, September 2013
pathogenesis of AD [19]. The role of cholesterol in the
pathogenesis of AD has been especially clarified by the findings
of genetic, epidemiological, and biology studies [37]. The
findings are supported by several genes involved in cholesterol
metabolism or transport as AD susceptibility genes, including
apolipoprotein E (ApoE), ApoJ, ATP-binding cassette subfamily
member 7 and sortilin-related receptor [37]. Clinical and basic
investigation reveals that cholesterol metabolism has a close
association with the progression of Alzheimer’s cognitive
impairment [38], A pathology [39] and NFTs induced by the
hyperphosphorylation of tau [40]. The biochemical literature
supports that cholesterol dyshomeostasis play crucial roles in
mediating the synaptic loss and cognitive deficits in AD [21], and
A pathology [41]. It well recognized that statins, as a class of
powerful regulators for cholesterol levels, play a neuroprotective
role in neurodegenerative process, such as Huntington's disease
(HD) [19], Parkinson’s disease, cerebral ischemia [42],
demyelinating disease, as well as AD [43]. Recent finding further
indicates that carriers of the KIF6 719Arg allele (Arg/Arg
homozygotes and Arg/Trp heterozygotes) is associated with the
effects of statins on cholesterol levels in amnestic mild cognitive
impairment and AD patients [44]. Research evidence indicates
that atorvastatin, a lipid-lowering agent of statins, prevents
cognitive impairments via improving hippocampal synaptic
function, and restores BBB integrity to enhance the clearance of
A by anti-inflammatory lipid-modulating process [45, 46].
Additional findings have evidenced that it is via limiting the
hyperphosphorylation of tau that satins act as the guardian of the
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brain lesions and neurodegenerative disorders. Overall,
cholesterol dyshomeostasis contributes to the pathogenesis of AD
and statins plays a neuroprotective role in the progression of AD
[38, 39, 47].
4. Statins: effective agents in limiting A pathology?
There is consensus within the AD research community that
amyloid plaques and NFTs are the major pathological features in
AD. AD pathogenesis is well accepted to be triggered and driven
by the production and deposition of A [5, 48]. Aβ is formed after
sequential cleavage of the amyloid precursor protein (APP) by
successive action of the β- and γ-secretases. In the amyloidogenic
pathway, APP is cleaved by β-secretase to produce sAPPβ and
subsequent cleavage by γ-secretase releases Aβ. In the
non-amyloidogenic pathway, -secretase cleaves APP to produce
secreted sAPPα and membrane-associated carboxy terminal
fragment alpha (CTFα), precluding Aβ generation. In most cases,
the predominant APP metabolic pathway is non-amyloidogenic
and secreted APP derivative is sAPPα.
For the reason that the research evidence points to a link between
cholesterol metabolism and AD and numerous studies indicate the
role of cholesterol in the process of A production and deposition
[49, 50], statins will be of great value via cholesterol-lowering
therapies as disease modifying agents [51]. The main mechanisms
include increased -secretase activity and decreased -secretase
and γ-secretase activity and non-lipid effects such as
anti-inflammation, anti-atherosclerotic actions, anti-oxidant and
anti-apoptosis ( Table 1 and Figure 1 ).
Figure 1 General assumption that statins limit A pathology. Statins could decrease β-secretase and γ-secretase, and inhibit amyloidogenic pathway
and limiting the Aβ releasing and the formation of amyloid plaques. Statins could increase α-secretase to limit the Aβ production in the
nonamyloidogenic pathway. Statins may also retard Aβ pathology via non-lipid effects such as anti-inflammation, anti-atherosclerotic actions,
anti-oxidant and anti-apoptosis, all of which are associated with Aβ pathology.
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N. Yan et al. /Aging and Neurodegeneration, Vol. 1 (1): 20-24, September 2013
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Table 1 Several agents of statins effect on A pathology
Agents of statins
Atorvastatin
Lovastatin
Simvastatin
Rosuvastatin
Mechanisms for limiting A pathology
Restoring BBB integrity via increasing nitric oxide and ApoE and enhancing the clearance of
A.
Stimulating the release of -secretase and soluble APP alpha (sAPP).
Lowing A level in cerebrospinal fluid in AD patients.
Decreased beta-cleaved C-terminal fragment
Involving alterations in the trafficking of APP and/or alterations in the activity of the proteases
that cleave APP.
Strongly reducing levels of A40 and A42 inhibiting -secretase
favoring the γ-secretase nonamyloidogenic pathway of APP processing
Modulating γ-secretase gene expression and APP processing in a human neuroglioma model
without affecting enzyme activity
4.1 Statins favor the -secretase nonamyloidogenic pathway
Research results implicate that statin treatment may favor the
-secretase nonamyloidogenic pathway of APP processing [53,
57, 58]. It is well known that -secretase non-amyloidogenic
pathway produces secreted sAPPα and impedes Aβ generation.
Scientific data suggests that statins may reinforce -secretase
activity via modifying the biophysical properties of plasma
membranes or modulating the function of unidentified protein
kinases [53]. In cultured neuroblastoma cells transfected with
human Swedish mutant APP, atorvastatin enhanced the release
of -secretase and soluble APPalpha (sAPP), and activated
the non-amyloidemic pathway [53]. Further evidence suggests
that statin drugs can boost α-secretase cleavage of APP via the
Rho/ROCK1 protein phosphorylation pathway.
4.2 Statins limit the amyloidogenic pathway
[55, 56]
[39, 57, 58]
[59]
[64], anti-atherosclerotic actions [65], anti-oxidant [64, 66] and
anti-apoptosis [40, 66, 67]. Statins significantly suppressed the
A-induced expression of interleukin-1beta (IL-1) and
inducible nitric oxide synthase (iNOS) and nitric oxide (NO) by
microglia and monocytes [64]. Statin administration also
significantly reduced the rac1-dependent activation of NADPH
oxidase and superoxide production [64]. As ApoE has been
found necessary for A pathology in in vivo and in vitro,
suppressing ApoE secretion by statins could inhibit the
production of A and the formation of amyloid plaques [68].
Additionally statins ( atorvastatin ) may restore blood-brain
barrier ( BBB ) integrity and enhancing the clearance of A
treatment for 2 and 8 weeks, indicated by a substantial
reduction of IgG and ApoB, particularly within the
hippocampus [45].
5. Discussion and perspective
Several studies demonstrated that statins limit the
amyloidogenic pathway via inhibiting the dimerization of
-secretase [60, 61]. At all concentrations of statins, the
statin-mediated reduction in A production was determined by
an inhibition of -secretase dimerization into its more active
form [60]. Research found that
treatment with atorvastatin may be beneficial for brain aging by
reducing beta-secretase-1 (BACE1) protein as BACE1 protein
levels and activity decreased and correlated with reduced brain
cholesterol [62]. Another study further demonstrated that
statins indirectly inhibit γ-secretase-mediated cleavage of
APP-CTFα and APP-CTFβ in in vitro and decrease the yield of
APP-CTFγ [63]. Considering a critical involvement of lipid raft
cholesterol in the modulation of APP processing by -secretase
and γ-secretase [37], statins may regulate lipid raft cholesterol
and effect on -secretase and γ-secretase resulting in altered Aβ
production.
4.3 Non-lipid effects of statins on Aβ pathology
Non-lipid effects of statins implicate the neuroprotective role
which statins attenuate A pathology via its anti-inflammation
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References
[45, 52-55]
There is a growing body of biological, epidemiological, and
clinical evidence that statins lowers serum cholesterol and
retard the pathogenesis of AD by a combination of different
cellular and systemic mechanisms that are based on the
inhibition of the biosynthesis of cholesterol and isoprenoid
by-products [17, 69, 70], and inhibiting the production of A by
disrupting secretase enzyme function and reducing
neuroinflammation [17, 38, 69-71]. However, recent results
suggest that statins may provide a slight benefit in the
prevention of AD and all-type dementia [72]. Even more
studies available indicate that statins have no benefit on AD [73,
74].
A
recent
large
randomized,
double-blind,
placebo-controlled multicenter trials showed that simvastatin
and atorvastatin have not confirmed a clinically demonstrable
cognitive benefit for statins in the treatment of AD [75].
Conversely statins induce intracellular accumulation of APP,
-secretase-cleaved
fragments,
and
A
via
an
isoprenoid-dependent mechanism [76]. Thus, the results of
research on this topic are inconsistent: some studies evidence
beneficial effects, but other studies do not.
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N. Yan et al. /Aging and Neurodegeneration, Vol. 1 (1): 20-24, September 2013
Meanwhile, there are a number of individual clinical cases
where cognition is clearly and reproducibly adversely affected
by statins although statins are considered as preventive
medicines for AD [62, 77, 78]. What’s the role of statins that
could help or hurt cognition? Furthermore, several evidence
reported that statins enhanced the development of A
pathology in spite of their limiting A pathology. Statin
medications were beneficial or harmful to Aβ pathology? It
appears that there is still a lot of work to do to discover the very
role of statin medications in clinical and preclinical research of
AD. It is actually unclear how much these agents can be helpful
or not for AD patients presently.
[14]
[15]
[16]
[17]
[18]
Acknowledgments
[19]
This work was supported, in part, by the Anhui Provincial
Nature Science Foundation (1308085MH158 to Z.C.).
[20]
[21]
Conflict of interest: None declared.
[22]
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
Gitto CA, Moroni MJ, Terezhalmy GT, Sandu S: The patient with
Alzheimer's disease. Quintessence Int 2001, 32(3):221-231.
Matsuda O, Saito M: Functional competency and cognitive ability in mild
Alzheimer's disease: relationship between ADL assessed by a relative/
carer-rated scale and neuropsychological performance. Int Psychogeriatr
2005, 17(2):275-288.
Saido TC: Metabolism of amyloid beta peptide and pathogenesis of
Alzheimer's disease. Proc Jpn Acad Ser B Phys Biol Sci 2013,
89(7):321-339.
Leuba G, Kraftsik R: Visual cortex in Alzheimer's disease: occurrence of
neuronal death and glial proliferation, and correlation with pathological
hallmarks. Neurobiol Aging 1994, 15(1):29-43.
Murphy MP, LeVine H, 3rd: Alzheimer's disease and the amyloid-beta
peptide. J Alzheimers Dis 2010, 19(1):311-323.
Belluti F, Rampa A, Gobbi S, Bisi A: Small-molecule
inhibitors/modulators of amyloid-beta peptide aggregation and toxicity
for the treatment of Alzheimer's disease: a patent review (2010 - 2012).
Expert Opin Ther Pat 2013, 23(5):581-596.
Schrotter A, Pfeiffer K, El Magraoui F, Platta HW, Erdmann R, Meyer
HE, Egensperger R, Marcus K, Muller T: The amyloid precursor protein
(APP) family members are key players in S-adenosylmethionine
formation by MAT2A and modify BACE1 and PSEN1 gene
expression-relevance for Alzheimer's disease. Mol Cell Proteomics 2012,
11(11):1274-1288.
Maloney B, Lahiri DK: The Alzheimer's amyloid beta-peptide (Abeta)
binds a specific DNA Abeta-interacting domain (AbetaID) in the APP,
BACE1, and APOE promoters in a sequence-specific manner:
characterizing a new regulatory motif. Gene 2011, 488(1-2):1-12.
Camnitz W, Burdick MD, Strieter RM, Mehrad B, Keeley EC:
Dose-dependent Effect of Statin Therapy on Circulating CXCL12 Levels
in Patients with Hyperlipidemia. Clin Transl Med 2012, 1(1):23.
Gelsinger C, Steinhagen-Thiessen E, Kassner U: Therapeutic potential of
mipomersen in the management of familial hypercholesterolaemia. Drugs
2012, 72(11):1445-1455.
Tandon N, Ali MK, Narayan KM: Pharmacologic prevention of
microvascular and macrovascular complications in diabetes mellitus:
implications of the results of recent clinical trials in type 2 diabetes. Am J
Cardiovasc Drugs 2012, 12(1):7-22.
Reiner Z: Managing the residual cardiovascular disease risk associated
with HDL-cholesterol and triglycerides in statin-treated patients: A
clinical update. Nutr Metab Cardiovasc Dis 2013.
Rosenson RS: Statin-induced lowering of LDL cholesterol associated
with a reduced risk for cardiovascular events, not likely outweighed by
ISSN 2331-2424 print/ISSN 2331-2432 online
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
- 23 -
- 23 -
the risk of diabetes, for people at low short-term risk of cardiovascular
disease. Evid Based Med 2013, 18(4):142-143.
Wierzbicki AS: Doubling up: maximising statin therapy as opposed to
adding other drugs for cardiovascular disease prevention. Int J Clin Pract
2013, 67(5):391-393.
Bittner V, Wenger NK, Waters DD, DeMicco DA, Messig M, LaRosa JC:
Retraction notice to "Vitamin D levels do not predict cardiovascular
events in statin-treated patients with stable coronary disease" [Am Heart J
2012;164:387-393]. Am Heart J 2013, 166(1):197.
de Ceniga MV, Blanco-Colio LM, Tunon J, Egido J, Martin-Ventura JL:
Statin use in aortic aneurismal disease to prevent progression and
cardiovascular events: review of experimental and clinical data C. Curr
Vasc Pharmacol 2013, 11(3):299-304.
Silva T, Teixeira J, Remiao F, Borges F: Alzheimer's disease, cholesterol,
and statins: the junctions of important metabolic pathways. Angew Chem
Int Ed Engl 2013, 52(4):1110-1121.
Wood WG, Igbavboa U, Muller WE, Eckert GP: Statins, Bcl-2, and
Apoptosis: Cell Death or Cell Protection? Mol Neurobiol 2013.
Vance JE: Dysregulation of cholesterol balance in the brain: contribution
to neurodegenerative diseases. Dis Model Mech 2012, 5(6):746-755.
Lukiw WJ: Amyloid beta (Abeta) peptide modulators and other current
treatment strategies for Alzheimer's disease (AD). Expert Opin Emerg
Drugs 2012.
Santos DB, Peres KC, Ribeiro RP, Colle D, dos Santos AA, Moreira EL,
Souza DO, Figueiredo CP, Farina M: Probucol, a lipid-lowering drug,
prevents cognitive and hippocampal synaptic impairments induced by
amyloid beta peptide in mice. Exp Neurol 2012, 233(2):767-775.
Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, Deng C, Yenari MA:
Statins: multiple neuroprotective mechanisms in neurodegenerative
diseases. Exp Neurol 2011, 230(1):27-34.
Florentin M, Tselepis AD, Elisaf MS, Rizos CV, Mikhailidis DP,
Liberopoulos EN: Effect of non-statin lipid lowering and anti-obesity
drugs on LDL subfractions in patients with mixed dyslipidaemia. Curr
Vasc Pharmacol 2010, 8(6):820-830.
Wee CC, Girotra S, Weinstein AR, Mittleman MA, Mukamal KJ: The
relationship between obesity and atherosclerotic progression and
prognosis among patients with coronary artery bypass grafts the effect of
aggressive statin therapy. J Am Coll Cardiol 2008, 52(8):620-625.
Alberton M, Wu P, Druyts E, Briel M, Mills EJ: Adverse events
associated with individual statin treatments for cardiovascular disease: an
indirect comparison meta-analysis. QJM 2012, 105(2):145-157.
Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP:
Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes
mellitus: the case for residual risk reduction after statin treatment. Open
Cardiovasc Med J 2011, 5:24-34.
Reyes-Soffer G, Rondon-Clavo C, Ginsberg HN: Combination therapy
with statin and fibrate in patients with dyslipidemia associated with
insulin resistance, metabolic syndrome and type 2 diabetes mellitus.
Expert Opin Pharmacother 2011, 12(9):1429-1438.
Mascitelli L, Goldstein MR: Long-standing statin therapy and the risk of
new-onset diabetes in the elderly: collateral damage caused by preventive
medicine? Drugs Aging 2012, 29(1):9-13.
Colbert JD, Stone JA: Statin use and the risk of incident diabetes mellitus:
a review of the literature. Can J Cardiol 2012, 28(5):581-589.
Butterfield DA, Barone E, Mancuso C: Cholesterol-independent
neuroprotective and neurotoxic activities of statins: perspectives for statin
use in Alzheimer disease and other age-related neurodegenerative
disorders. Pharmacol Res 2011, 64(3):180-186.
Hou W, Lv J, Perkovic V, Yang L, Zhao N, Jardine MJ, Cass A, Zhang H,
Wang H: Effect of statin therapy on cardiovascular and renal outcomes in
patients with chronic kidney disease: a systematic review and
meta-analysis. Eur Heart J 2013, 34(24):1807-1817.
Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW,
Cote N, Mathieu P, Despres JP, Pibarot P: Impact of metabolic syndrome
on progression of aortic stenosis: influence of age and statin therapy. J
Am Coll Cardiol 2012, 60(3):216-223.
Devaraj S, Siegel D, Jialal I: Statin therapy in metabolic syndrome and
hypertension post-JUPITER: what is the value of CRP? Curr Atheroscler
Rep 2011, 13(1):31-42.
Zeliger H: Statin use and risk of diabetes. Arch Intern Med 2012,
172(11):896; author reply 896-897.
Rajpathak SN: Intensive statin therapy, compared with moderate dose,
increases risk of new onset diabetes but decreases risk of cardiovascular
events. Evid Based Med 2012, 17(2):55-56.
http://www.researchpub.org/journal/and/and.html
N. Yan et al. /Aging and Neurodegeneration, Vol. 1 (1): 20-24, September 2013
[36] Roy A, Pahan K: Prospects of statins in Parkinson disease. Neuroscientist
2011, 17(3):244-255.
[37] Reitz C: Dyslipidemia and the risk of Alzheimer's disease. Curr
Atheroscler Rep 2013, 15(3):307.
[38] Scott HD, Laake K: Statins for the prevention of Alzheimer's disease.
Cochrane Database Syst Rev 2001(4):CD003160.
[39] Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P,
Runz H, Kuhl S, Bertsch T, von Bergmann K 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 U S A 2001,
98(10):5856-5861.
[40] Meske V, Albert F, Richter D, Schwarze J, Ohm TG: Blockade of
HMG-CoA reductase activity causes changes in microtubule-stabilizing
protein tau via suppression of geranylgeranylpyrophosphate formation:
implications for Alzheimer's disease. Eur J Neurosci 2003, 17(1):93-102.
[41] Reitz C: Dyslipidemia and dementia: current epidemiology, genetic
evidence, and mechanisms behind the associations. J Alzheimers Dis
2012, 30 Suppl 2:S127-145.
[42] McCarty MF: Up-regulation of endothelial nitric oxide activity as a
central strategy for prevention of ischemic stroke - just say NO to stroke!
Med Hypotheses 2000, 55(5):386-403.
[43] Cucchiara B, Kasner SE: Use of statins in CNS disorders. J Neurol Sci
2001, 187(1-2):81-89.
[44] Sabbagh M, Malek-Ahmadi M, Levenson I, Sparks DL: KIF6 719Arg
allele is associated with statin effects on cholesterol levels in amnestic
mild cognitive impairment and Alzheimer's disease patients. J Alzheimers
Dis 2013, 33(1):111-116.
[45] Pallebage-Gamarallage M, Lam V, Takechi R, Galloway S, Clark K,
Mamo J: Restoration of dietary-fat induced blood-brain barrier
dysfunction by anti-inflammatory lipid-modulating agents. Lipids Health
Dis 2012, 11:117.Santulli G. The Ten Commandments of Ethical
Publishing. Cell and Developmental biology 2012;1:1.
[46] Stuve O, Youssef S, Steinman L, Zamvil SS: Statins as potential
therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol
2003, 16(3):393-401.
[47] Crisby M, Carlson LA, Winblad B: Statins in the prevention and
treatment of Alzheimer disease. Alzheimer Dis Assoc Disord 2002,
16(3):131-136.
[48] Moro ML, Collins MJ, Cappellini E: Alzheimer's disease and amyloid
beta-peptide deposition in the brain: a matter of 'aging'? Biochem Soc
Trans 2010, 38(2):539-544.
[49] Hoglund K, Blennow K: Effect of HMG-CoA reductase inhibitors on
beta-amyloid peptide levels: implications for Alzheimer's disease. CNS
Drugs 2007, 21(6):449-462.
[50] Kuller LH: Statins and dementia. Curr Atheroscler Rep 2007,
9(2):154-161.
[51] Petanceska SS, DeRosa S, Olm V, Diaz N, Sharma A, Thomas-Bryant T,
Duff K, Pappolla M, Refolo LM: Statin therapy for Alzheimer's disease:
will it work? J Mol Neurosci 2002, 19(1-2):155-161.
[52] Kirsch C, Eckert GP, Koudinov AR, Muller WE: Brain cholesterol,
statins and Alzheimer's Disease. Pharmacopsychiatry 2003, 36 Suppl
2:S113-119.
[53] Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo L, Buxbaum JD,
Bogush A, Petanceska S, Gandy S: Atorvastatin-induced activation of
Alzheimer's alpha secretase is resistant to standard inhibitors of protein
phosphorylation-regulated ectodomain shedding. J Neurochem 2004,
90(4):1005-1010.
[54] Hoglund K, Syversen S, Lewczuk P, Wallin A, Wiltfang J, Blennow K:
Statin treatment and a disease-specific pattern of beta-amyloid peptides in
Alzheimer's disease. Exp Brain Res 2005, 164(2):205-214.
[55] Burns MP, Igbavboa U, Wang L, Wood WG, Duff K: Cholesterol
distribution, not total levels, correlate with altered amyloid precursor
protein processing in statin-treated mice. Neuromolecular Med 2006,
8(3):319-328.
[56] Buxbaum JD, Geoghagen NS, Friedhoff LT: Cholesterol depletion with
physiological concentrations of a statin decreases the formation of the
Alzheimer amyloid Abeta peptide. J Alzheimers Dis 2001, 3(2):221-229.
[57] Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P,
Wallin A, Blennow K: Treatment with simvastatin in patients with
ISSN 2331-2424 print/ISSN 2331-2432 online
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
- 24 -
- 24 -
Alzheimer's disease lowers both alpha- and beta-cleaved amyloid
precursor protein. Dement Geriatr Cogn Disord 2003, 16(1):25-30.
Hoglund K, Thelen KM, Syversen S, Sjogren M, von Bergmann K,
Wallin A, Vanmechelen E, Vanderstichele H, Lutjohann D, Blennow K:
The effect of simvastatin treatment on the amyloid precursor protein and
brain cholesterol metabolism in patients with Alzheimer's disease.
Dement Geriatr Cogn Disord 2005, 19(5-6):256-265.
Crestini A, Piscopo P, Iazeolla M, Albani D, Rivabene R, Forloni G,
Confaloni A: Rosuvastatin and thapsigargin modulate gamma-secretase
gene expression and APP processing in a human neuroglioma model. J
Mol Neurosci 2011, 43(3):461-469.
Parsons RB, Price GC, Farrant JK, Subramaniam D, Adeagbo-Sheikh J,
Austen BM: Statins inhibit the dimerization of beta-secretase via both
isoprenoid- and cholesterol-mediated mechanisms. Biochem J 2006,
399(2):205-214.
Sidera C, Parsons R, Austen B: The regulation of beta-secretase by
cholesterol and statins in Alzheimer's disease. J Neurol Sci 2005,
229-230:269-273.
Murphy MP, Morales J, Beckett TL, Astarita G, Piomelli D, Weidner A,
Studzinski CM, Dowling AL, Wang X, Levine H, 3rd et al: Changes in
cognition and amyloid-beta processing with long term cholesterol
reduction using atorvastatin in aged dogs. J Alzheimers Dis 2010,
22(1):135-150.
Zhou Y, Suram A, Venugopal C, Prakasam A, Lin S, Su Y, Li B, Paul SM,
Sambamurti
K:
Geranylgeranyl
pyrophosphate
stimulates
gamma-secretase to increase the generation of Abeta and
APP-CTFgamma. FASEB J 2008, 22(1):47-54.
Cordle A, Landreth G: 3-Hydroxy-3-methylglutaryl-coenzyme A
reductase inhibitors attenuate beta-amyloid-induced microglial
inflammatory responses. J Neurosci 2005, 25(2):299-307.
Yildirir A, Muderrisoglu H: Non-lipid effects of statins: emerging new
indications. Curr Vasc Pharmacol 2004, 2(4):309-318.
Ramirez C, Tercero I, Pineda A, Burgos JS: Simvastatin is the statin that
most efficiently protects against kainate-induced excitotoxicity and
memory impairment. J Alzheimers Dis 2011, 24(1):161-174.
Stefani M, Liguri G: Cholesterol in Alzheimer's disease: unresolved
questions. Curr Alzheimer Res 2009, 6(1):15-29.
Naidu A, Xu Q, Catalano R, Cordell B: Secretion of apolipoprotein E by
brain glia requires protein prenylation and is suppressed by statins. Brain
Res 2002, 958(1):100-111.
Sanchez-Ferro A, Benito-Leon J, Mitchell AJ, Bermejo-Pareja F: A
review of the potential therapeutic role of statins in the treatment of
Alzheimer's disease: current research and opinion. Neuropsychiatr Dis
Treat 2013, 9:55-63.
Pac-Soo C, Lloyd DG, Vizcaychipi MP, Ma D: Statins: the role in the
treatment and prevention of Alzheimer's neurodegeneration. J Alzheimers
Dis 2011, 27(1):1-10.
Scott HD, Laake K: Statins for the reduction of risk of Alzheimer's
disease. Cochrane Database Syst Rev 2001(3):CD003160.
Wong WB, Lin VW, Boudreau D, Devine EB: Statins in the prevention of
dementia and Alzheimer's disease: a meta-analysis of observational
studies and an assessment of confounding. Pharmacoepidemiol Drug Saf
2013, 22(4):345-358.
McGuinness B, Passmore P: Can statins prevent or help treat Alzheimer's
disease? J Alzheimers Dis 2010, 20(3):925-933.
Whitfield JF: Can statins put the brakes on Alzheimer's disease? Expert
Opin Investig Drugs 2006, 15(12):1479-1485.
Sabbagh MN, Sparks DL: Statins to treat Alzheimer's disease: an
incomplete story. Expert Rev Neurother 2012, 12(1):27-30.
Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R: Statins
cause intracellular accumulation of amyloid precursor protein,
beta-secretase-cleaved fragments, and amyloid beta-peptide via an
isoprenoid-dependent
mechanism.
J
Biol
Chem
2005,
280(19):18755-18770.
Biondi E: Statin-like drugs for the treatment of brain cholesterol loss in
Alzheimer's disease. Curr Drug Saf 2007, 2(3):173-176.
Miida T, Takahashi A, Tanabe N, Ikeuchi T: Can statin therapy really
reduce the risk of Alzheimer's disease and slow its progression? Curr
Opin Lipidol 2005, 16(6):619-623
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