Statins are Protective Against Beta-amyloid Pathology in Alzheimer`s

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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)
ISSN 2331-2424 print/ISSN 2331-2432 online
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]
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