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Resveratrol and Amyloid-Beta: Mechanistic Insights

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The amyloid-beta (Aβ) hypothesis that dyshomeostasis between Aβ production and clearance is a very early, key molecular factor in the etiology of Alzheimer’s disease (AD) has been proposed and examined in the AD research field. Scientists have focused on seeking natural products or drugs to influence the dynamic equilibrium of Aβ, targeting production and clearance of Aβ. There is emerging evidence that resveratrol (Res), a naturally occurring polyphenol mainly found in grapes and red wine, acts on AD in numerous in vivo and in vitro models. Res decreases the amyloidogenic cleavage of the amyloid precursor protein (APP), enhances clearance of amyloid beta-peptides, and reduces Aβ aggregation. Moreover, Res also protects neuronal functions through its antioxidant properties. This review discusses the action of Res on Aβ production, clearance and aggregation and multiple potential mechanisms, providing evidence of the useful of Res for AD treatment.
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nutrients
Review
Resveratrol and Amyloid-Beta: Mechanistic Insights
Yongming Jia 1ID , Na Wang 2and Xuewei Liu 1, *ID
1Department of Neuropharmacology, Research Institute of Medicine and Pharmacy, Qiqihar Medical
University, Qiqihar 161006, China; yongmingjiahlj@126.com
2Department of Pathophysiology, Qiqihar Medical University, Qiqihar 161006, China;
christina85721@163.com
*Correspondence: lxw_qmu@126.com; Tel./Fax: +86-452-2663619
Received: 19 August 2017; Accepted: 2 October 2017; Published: 14 October 2017
Abstract:
The amyloid-beta (A
β
) hypothesis that dyshomeostasis between A
β
production and
clearance is a very early, key molecular factor in the etiology of Alzheimer’s disease (AD) has been
proposed and examined in the AD research field. Scientists have focused on seeking natural products
or drugs to influence the dynamic equilibrium of A
β
, targeting production and clearance of A
β
.
There is emerging evidence that resveratrol (Res), a naturally occurring polyphenol mainly found
in grapes and red wine, acts on AD in numerous
in vivo
and
in vitro
models. Res decreases the
amyloidogenic cleavage of the amyloid precursor protein (APP), enhances clearance of amyloid
beta-peptides, and reduces A
β
aggregation. Moreover, Res also protects neuronal functions through
its antioxidant properties. This review discusses the action of Res on A
β
production, clearance
and aggregation and multiple potential mechanisms, providing evidence of the useful of Res for
AD treatment.
Keywords: resveratrol; amyloid-beta; alzheimer disease; transporter; blood-brain-barrier
1. Introduction
Alzheimer’s disease (AD) is considered the most frequent form of dementia, affecting
more than 35.6 million people worldwide and becoming an emerging burden on society [
1
,
2
].
Although researchers have delved into all aspects of this complex, multifactorial syndrome in
recent years, the exact molecular events underlying AD remain to be exhaustively elucidated.
The amyloid-beta (A
β
) hypothesis which synthesizes histopathological and genetic information has
become the dominant model of AD pathogenesis and is guiding the development of a novel strategy
in the treatment of AD [
3
]. The pathological accumulation of A
β
in the brain leads to impairment
of synaptic function and structure, progressive tau deposition, neuronal destruction and finally the
clinical symptoms of AD [
3
]. A
β
homeostasis in the brain is governed by its production and clearance
mechanisms [
4
]. A
β
was produced by sequential scission of amyloid precursor protein (APP) by
the
β
-APP cleaving enzyme (BACE) and
γ
-secretase [
5
]. Numerous pathways have been reported to
play roles in A
β
clearance and degradation, including autophagic pathway and receptor-mediated
endocytosis [
6
]. Some proteins with a crucial role in A
β
clearance are A
β
-degrading enzymes (ADEs),
which could degrade or cleave A
β
into smaller fragments, and lipoprotein receptor-related protein 1
(LRP1), which regulates metabolism of A
β
and brain homeostasis through multiple pathways and
transporters such as P-glycoprotein (P-gp), localized in astrocytes and on the abluminal side of the
cerebral endothelium, where they transport A
β
from brain to blood [
7
9
]. So some researchers focused
on screening drugs which can influence the dynamic equilibrium of A
β
, targeting production and
clearance of Aβ.
Resveratrol (3,5,4’-trihydroxy-trans-stilbene, Res), a naturally polyphenolic phytoalexin,
abundantly found in grapes, berries, red wine and many other plant species, shows diverse biological
Nutrients 2017,9, 1122; doi:10.3390/nu9101122 www.mdpi.com/journal/nutrients
Nutrients 2017,9, 1122 2 of 13
activities such as antioxidant, anticarcinogenic and anti-inflammatory properties, and so on [
10
].
Recent evidence found that, in various
in vitro
and
in vivo
models of AD, Res plays a prominent role
in the prevention and treatment of AD [
11
,
12
]. Res attenuated A
β
-induced cytotoxicity, apoptosis and
intracellular reactive oxygen intermediate (ROI) accumulation in PC12 cells [
13
]. Similarly, Res inhibits
A
β
-induced neuronal apoptosis in PC12 cells through regulation of silent information regulator 1
(SIRT1)-Rho-associated kinase 1 (ROCK1) signaling pathway [
14
]. In Res-treated APP/PS1 mice which
are a model of cerebral A
β
deposition, there was a significant reduction in the number of activated
microglia, providing anti-inflammatory effects of Res against A
β
-triggered microglial activation [
15
].
It is interesting that A
β
accumulation in the brain has been shown to induce cytotoxicity, apoptosis
and activation of astrocytes in cell and animal models [
16
18
]. So we explore whether Res can affect
A
β
accumulation and aggregation in AD model (Tables 1and 2). In this review, we discuss the effects
of Res on A
β
production and clearance and clarify those multiple mechanisms in various models and
explore Res as a new drug candidate in AD treatment.
2. The Source and Pharmacological Profile of Res
Res belongs to the stilbene family of phytoalexins produced by various plants in response to
environmental stress, which have been detected in at least 72 plant species, especially grape vines,
pine trees, jackfruit, blueberry, cranberry, and mulberry [
19
,
20
]. Res containing two aromatic rings
in its structure exists in two isomers: trans-Res, which has been most widely studied, and cis-Res;
the trans form is more stable and potent than the cis form, which may have different biological effects
(Figure 1) [
21
]. Res has diverse biological activities and is not known to cause significant adverse
effects in experimental animals and humans [
22
24
]. A clinical trial found that oral Res at a single dose
of 5 g in 10 healthy volunteers resulted in no apparent adverse effects, and the peak level of Res in
plasma was 539 ng/mL, while plasma concentration of two Res monoglucuronides and Res 3-sulfate
were 1285 ng/mL, 1735 ng/mL, 4294 ng/mL, respectively [
22
]. Similarly, a double-blind, randomized,
placebo-controlled study showed that Res is safe in healthy individuals, but produced a relatively
low plasma concentration. Res exhibits low oral bioavailability due to its rapid metabolism and
elimination, which is rapidly metabolized by conjugation to glucuronic acid and/or sulfate, forming
Res glucuronides, sulfates, and/or sulfoglucuronides [
25
]. Thus, Res analogues and inhibitors affecting
Res metabolism were developed to enhance its bioavailability.
Nutrients 2017, 9, 1122 2 of 13
Resveratrol (3,5,4-trihydroxy-trans-stilbene, Res), a naturally polyphenolic phytoalexin,
abundantly found in grapes, berries, red wine and many other plant species, shows diverse biological
activities such as antioxidant, anticarcinogenic and anti-inflammatory properties, and so on [10].
Recent evidence found that, in various in vitro and in vivo models of AD, Res plays a prominent role
in the prevention and treatment of AD [11,12]. Res attenuated Aβ-induced cytotoxicity, apoptosis
and intracellular reactive oxygen intermediate (ROI) accumulation in PC12 cells [13]. Similarly, Res
inhibits Aβ-induced neuronal apoptosis in PC12 cells through regulation of silent information
regulator 1 (SIRT1)-Rho-associated kinase 1 (ROCK1) signaling pathway [14]. In Res-treated APP/PS1
mice which are a model of cerebral Aβ deposition, there was a significant reduction in the number of
activated microglia, providing anti-inflammatory effects of Res against Aβ-triggered microglial
activation [15]. It is interesting that Aβ accumulation in the brain has been shown to induce
cytotoxicity, apoptosis and activation of astrocytes in cell and animal models [1618]. So we explore
whether Res can affect Aβ accumulation and aggregation in AD model (Tables 1 and 2). In this
review, we discuss the effects of Res on Aβ production and clearance and clarify those multiple
mechanisms in various models and explore Res as a new drug candidate in AD treatment.
2. The Source and Pharmacological Profile of Res
Res belongs to the stilbene family of phytoalexins produced by various plants in response to
environmental stress, which have been detected in at least 72 plant species, especially grape vines,
pine trees, jackfruit, blueberry, cranberry, and mulberry [19,20]. Res containing two aromatic rings in
its structure exists in two isomers: trans-Res, which has been most widely studied, and cis-Res; the
trans form is more stable and potent than the cis form, which may have different biological effects
(Figure 1) [21]. Res has diverse biological activities and is not known to cause significant adverse
effects in experimental animals and humans [2224]. A clinical trial found that oral Res at a single
dose of 5 g in 10 healthy volunteers resulted in no apparent adverse effects, and the peak level of Res
in plasma was 539 ng/mL, while plasma concentration of two Res monoglucuronides and Res
3-sulfate were 1285 ng/mL, 1735 ng/mL, 4294 ng/mL, respectively [22]. Similarly, a double-blind,
randomized, placebo-controlled study showed that Res is safe in healthy individuals, but produced
a relatively low plasma concentration. Res exhibits low oral bioavailability due to its rapid
metabolism and elimination, which is rapidly metabolized by conjugation to glucuronic acid and/or
sulfate, forming Res glucuronides, sulfates, and/or sulfoglucuronides [25]. Thus, Res analogues and
inhibitors affecting Res metabolism were developed to enhance its bioavailability.
Figure 1. Isomers of resveratrol.
Figure 1. Isomers of resveratrol.
Nutrients 2017,9, 1122 3 of 13
Table 1. Neuroprotective effects of resveratrol in Alzheimer ’s disease (AD) models in vivo.
Experimental Animal Model/Method Action of Resveratrol Dosage Duration of Treatment Reference
APP/PS1 mice AD Inhibits Aβ-mediated microglial activation AIN-93G diet supplemented with
0.35% resveratrol 15 weeks [15]
Sprague-Dawley rats - increases PSEN1 expression in the rat brain dietary resveratrol 28 days [26]
Mice Injected with
lipopolysaccharide increases both the estradiol level and NEP level injected with resveratrol 4 mg/kg 7 days [27]
APP/transthyretin (TTR) mice AD Increased LRP1 expression upregulated and stabilizes TTR 174 mg/kg/day 2 months [28]
Wistar female rats AD
decreases level of insoluble Aβin the hippocampus
80 mg/kg 12 weeks [29]
reduces the expression of RAGE in the hippocampus
inhabits the expression of MMP-9
A
β
: amyloid-beta; NEP: neprilysin; APP: amyloid precursor protein; LRP1: lipoprotein receptor-related protein 1; RAGE: the receptor for advanced glycation end products; MMP-9:
matrix metalloprotein-9.
Table 2. Mechanism of resveratrol on amyloid-beta (Aβ) production and clearance in vitro.
Experimental Model/Method Exposure Mechanism of Resveratrol Dosage of Resveratrol Duration of Resveratrol
Treatment Reference
PC12 cells Aβ25–35 induced attenuated Aβ-induced cytotoxicity, apoptotic
features, and intracellular ROI accumulation. 25 µM 24 h [13]
PC12 cells Aβ25–35 induced
inhibited the cell apoptosis
12.5–100 µM24–48 h [14]
prevented the LDH leakage
maintained the intracellular Ca2+ homeostasis
Purified baculovirus-expressed BACE-1 - inhibition of BACE-1 11.9 µM (IC50) - [30]
TRF assay - inhibition of BACE-1 28 µM (IC50) 30 min [31]
Neuro2a cells HEK293 transfected with a plasmid
containing APPsw
reduced γ-secretase activity 2.5–20 µM24 h [32]
induced MMP-9 activation
autophagy-related 5 knockdown HEK293 -
induced conversion of LC3-I to LC3-II
60 µM24 h [33]
suppression of Presenilin-1 induction
suppressed Aβproduction
SK-N-SH cells - induction of NEP and ACE activity 10 µM 4 days [34]
Hippocampal samples from AD patients AD binds to both fibril and monomer Aβ1.56–100 µM - [35]
ROI: reactive oxygen intermediate; BACE: β-APP cleaving enzyme.
Nutrients 2017,9, 1122 4 of 13
3. Effect of Res on AβProduction
3.1. Inhibitory Activity against BACE1
BACE1, mainly expressed in neurons of the brain, exhibited all the known characteristics of the
β
-secretase, which cleave extracellular of APP important in the pathogenesis of AD [
36
]. Tamagno et al.
reported that A
β
induces production of oxidative stress markers 4-hydroxynonenal and upregulates
BACE-1 expression in NT2 neuronal cells, further fostering amyloidogenic processing of APP, thereby
increasing accumulation of A
β
[
37
]. Scientists hope to find some active compounds or develop new
drugs to block BACE1 (BACE inhibitors), further decreasing A
β
accumulation, regarding BACE as
a key target for AD treatment. Studies showed that Res and Res oligomers significantly inhibited
BACE activity in a dose dependent manner, which was assessed by fluorescence resonance energy
transfer (FRET) assay [
30
]. Similarly, Koukoulitsa et al. found that Res and its derivatives bearing one
(tert-butyl, 1-ethylpopyl) or two bulky electron donating groups ortho to 4’-OH displayed different
potencies against BACE1 using time-resolved fluorescence (TRF) assay, further suggesting that Res
can inhibit BACE1 function [
31
,
38
]. In contrast, Marambaud et al. found that Res does not inhibit
A
β
production through neither affecting
β
- nor
γ
-secretases [
39
]. The paradoxical results may be
caused by different methods and cells, which need further studies. Some potent BACE1 inhibitors
is now undergoing clinical trials such as E2609, AZD3293 and LY2886721, and some adverse effects
also reported [
40
]. Finding active components such as Res in herbs targeting
β
-secretases could be
a strategy in AD treatment.
3.2. Inhibitory Activity against γ-Secretase
γ
-Secretases are a family of intramembrane cleaving aspartyl proteases, consisting of four
subunits presenilin (PSEN), anterior pharynx defective-1, nicastrin, and presenilin enhancer-2 [
41
].
When the expression and activity of those four subunits were changed, the catalytic function of
γ
-secretases could also be changed [
42
]. Recent evidence showed that rats fed with Res, a SIRT1
inducer, exhibit a significant increase in PSEN1 expression, which is one of SIRT1-specific DNA
targets [
26
]. Unfortunately, the results did not show whether the activity of
γ
-secretase was changed
and A
β
production could be suppressed by SIRT1 [
26
]. Choi et al. found that Res (5–20
µ
M)
as well as its analogues inhibit
γ
-secretase activity and increase
α
-secretase activity in Neuro2a
neuroblastoma cells, which may be associated with a decrease in A
β
levels, without causing cell
death [
32
]. However, another study showed that Res has no effect on
γ
-secretases, without affecting
Aβproduction and APP metabolism [39].
3.3. Autophagy Induction
Emerging evidence indicated that autophagy pathways could affect developmental and
neurodegenerative processes, including AD. AD etiology is also associated with damaged
mitochondria in the neurons. Misfolded proteins translocated and accumulated into the mitochondrial
membrane, leading to the disruption of oxidative phosphorylation and then autophagy activation [
43
].
Accordingly, neuronal autophagy is known to play key roles in synaptic plasticity, anti-inflammatory
function in glial cells, oligodendrocyte development, and myelination process [
44
]. Studies found that a
decline in autophagy efficiency during aging led to accumulation of A
β
and cytochrome c release in the
mitochondrial membrane, resulting cell death and neurodegeneration [
45
,
46
]. Moreover, accumulation
of pathological autophagic vacuoles can be observed in PS1/APP mouse AD model [
47
]. Imbalance
between autophagic flux and degradation result in decreased proteolysis of A
β
[
48
]. In AD, autophagy
impairment stimulates PSEN1 expression and then increases γ-secretase activity, leading to augment
of A
β
synthesis [
49
]. Res, an autophagy inducer, decreased PSEN1 expression, consistent with
a suppression of A
β
production [
33
]. Moreover, Res can activate tyrosyl transferRNA (tRNA)
synthetase (TyrRS)-auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1 (PARP1)-SIRT1
Nutrients 2017,9, 1122 5 of 13
signaling pathway, inducing autophagy in PC12 cells, thereby attenuating neurotoxicity caused by
Aβ[50]. Res have the therapeutic potential of AD through activating autophagy.
4. Effect of Res on AβClearance
Metabolic pathway of A
β
in AD pathogenesis, especially in late-onset sporadic AD (LOAD) has
been raised, and the main mechanisms of A
β
clearance have been considered as new therapeutic
targets [
51
,
52
]. Res could modulate A
β
clearance in various ways such as activation of ADEs, transport
across the blood-brain barrier (BBB) into the circulation, uptake by microglial phagocytosis and
inhibition of Aβaggregation [53,54].
4.1. Activation of ADEs
Disturbances in the activity of ADEs, including neprilysin (NEP), insulin-degrading enzyme
(IDE), angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE) and plasmin, could
induce A
β
accumulation, resulting in AD pathology [
55
,
56
]. Activity of ADEs could be affected by
Res in different AD models.
In vitro
studies, NEP and ACE activities were induced effectively in
SK-N-SH cells with low concentrations of Res for 4 days [
34
]. The authors found that Res enhances the
differentiation state of proliferating cells, which correlated with up-regulation of the cellular enzymatic
activity to enhance NEP and ACE activity [
34
]. Similarly, Marambaud found that NEP activity was
significantly increased after Res treatment on intact HEK293 cells. However, proteasomal degradation
pathway might involve in Res-mediated decrease of A
β
but not the increased NEP activity induced
by Res [
16
]. Moreover, study found that in human endothelial cells, Res decreased ECE-1 mRNA
expression and reduced ECE-1 activity, further affecting endothelin synthesis and conversion; however,
incubation concentration of Res (30
µ
M) cannot achieve in rat and/or human plasma [
57
]. Although
ECE-1 activity can be inhibited by Res, it cannot induce A
β
accumulation in brain, leading to AD.
In vivo
study, Res could dramatically increase both the estradiol level and NEP level in LPS-treated rats
and control rats using NEP ELISA kit [
27
]. Those results indicated that Res can involve in activation of
ADEs, but whether Res promotes clearance of Aβthrough ADEs needs further studies.
4.2. Plasminogen System
The plasminogen system is a complex enzymatic cascade [
58
]. Plasmin (PL), degrading many
plasma proteins, is an important serine protease released from the inactive zymogen plasminogen
(PLG) by two physiological activators tissue-type plasminogen activator (t-PA) and urokinase-type
plasminogen activator (u-PA) [
59
]. Function of t-PA and u-PA were controlled by PA inhibitor type 1
(PAI-1) and type 2 (PAI-2) [
60
]. PL is involved in many pathophysiological processes through its ability
to cleave fibrin, fibronectin, thrombospondin, laminin, and von Willebrand factor. The plasminogen
system has been implicated in neuronal plasticity and long-term potentiation (LTP) in the brain [
61
].
Studies showed that tPA-plasmin system contributes to the clearance of A
β
in mouse brain and
the prevention of A
β
-induced neurotoxicity, suggesting that the plasminogen system is associated
with late-onset AD [
62
]. Similarly, polymorphisms in the u-PA gene have been associated with
AD susceptibility [
63
]. Res increased plasminogen activators t-PA and u-PA expression in cultured
human umbilical vein endothelial cells (HUVECs), leading to plasminogen endoproteolysis and
plasmin activation.
4.3. Neurovascular Pathways
The neurovascular unit (NVU) consists of different cell types, including brain endothelial cells,
glial cells and neurons, which controls BBB permeability, neurovascular coupling and clearance
of toxins such as A
β
from brain [
64
]. BBB permeability controls entry from blood and promotes
clearance of macromolecules from the brain [
64
]. Moreover, transporters and receptors in the brain
endothelium regulate delivery of drugs and endogenous substances in the brain. Studies have
shown that A
β
is a substrate of LRP1, the receptor for advanced glycation end products (RAGE)
Nutrients 2017,9, 1122 6 of 13
and several ABC transporters such as P-gp and Breast cancer resistance protein (BCRP) [
65
68
].
Under physiological conditions, vascular damage and changes in the expression of several BBB
transporters and receptors could affect A
β
transport from blood-to-brain and/or brain-to-blood.
Res, a novel transporter modulator, defends BBB integrity and changes transporter and receptors
expressions in BBB, thereby regulating A
β
homeostasis [
28
,
65
]. We will focus on effect of Res on:
(1) integrity of BBB, which regulates delivery of energy metabolites and essential nutrients; (2) ABC
transporters in brain that mediate A
β
efflux into circulation from brain; (3) LRP1 mediating A
β
efflux from brain; and (4) RAGE, which mediates A
β
reentry into the brain from circulation and the
neurovascular inflammatory response.
4.3.1. BBB Integrity
Several studies have suggested that injured BBB integrity and cerebrovascular dysfunction lead to
faulty A
β
clearance from the brain [
69
]. Res could protect BBB integrity in different animal models [
70
].
In ovariectomized + D-galactose induced rat model of AD, Res decreases the insoluble A
β42
level
and protects the BBB integrity through regulating the expressions of RAGE, matrix metalloprotein-9
(MMP-9) and Claudin-5 [
29
]. In clinic, Res appears to restore BBB integrity in AD patients, reducing the
ability of harmful immune molecules secreted by immune cells to infiltrate from the body [
71
]. Similarly,
Res has exhibited restoration of BBB integrity via reduction of MMP-9 and induce adaptive immune
responses which may promote brain resilience to A
β
deposition in AD patients [
72
]. Those studies
suggested that Res could protect BBB integrity, changing Aβhomeostasis.
4.3.2. P-gp
In vitro
and
in vivo
studies showed that eliminated P-gp, first ABC transporter detected in
endothelial cells of the human BBB lead to A
β
accumulation [
9
,
73
]. Furthermore, P-gp activity at
the BBB is reduced in AD individuals [
74
], suggesting that impaired P-gp activity may mediate
cerebral A
β
accumulation. Our previous studies indicated that Res enhanced bestatin absorption by
downregulating P-gp expression in Caco-2 cells [
10
]. Moreover, Res and its major metabolites could
penetrate BBB and be measured in Cerebrospinal fluid (CSF) in AD patients [
75
], at least indicating
that Res has the opportunity to have CNS effects. Unfortunately, no effects of Res treatment on A
β42
level in plasma and CSF has been detected [
75
], and no research has yet investigated whether P-gp
expression at the BBB is changed by Res. A larger study is required to determine whether Res can
affect Aβclearance through regulating P-gp.
4.3.3. LRP1
LRP1, one receptor in the LDL receptor family, is not only a multifunctional scavenger and
cargo transporter but also has signal transduction activity [
76
]. As a cargo transporter, some studies
have reported that LRP1 transported several ligands from brain to blood including A
β
[
77
,
78
].
Moreover, several genetic studies have indicated that LRP1 expression at the BBB is reduced in
AD and have been considered as a therapeutic target in AD [
79
,
80
]. After treatment with Res in AD
transgenic female mice, the brain LRP1 protein expression was increased, while its mRNA was not
changed [
28
]. The author further found that Res could upregulate and stabilize transthyretin (TTR)
which binds A
β
peptide avoiding its aggregation and toxicity, resulting increased LRP1 [
28
].
In vitro
studies, LRP1 mediated the cytotoxicity of the fibrillar A
β
oligomers following their binding to prion
protein (PrP
C
), and Res could reduce PrP
C
and LRP1-mediated binding in SH-SY5Y cells, remodeling
the fibrillar Aβoligomer conformation [81].
4.3.4. RAGE
RAGE, a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, binds
distinct classes of ligands such as AGE proteins and A
β
[
82
]. RAGE expressed at the luminal side of
the BBB transport A
β
from the blood into the brain. In addition, intraneuronal transport of A
β
via
Nutrients 2017,9, 1122 7 of 13
neuronal RAGE leads to mitochondrial dysfunction [
83
]. RAGE expression is increased in the AD
capillary under pathological conditions. Res has been shown to reduce RAGE expression in vascular
cells [
84
]. Scientists are now comfortable referring to AD as type 3 diabetes, which results from insulin
resistance in the brain. Similarly, Res can also downregulate RAGE expression in the kidney and liver
of rats with type 2 diabetes [
85
,
86
]. However, whether RAGE expression triggered by Res could affect
A
β
uptake, leading to A
β
accumulation in brain needs further research. Given the important role of
RAGE in A
β
accumulation in AD, finding drugs which can block RAGE may contribute to control of
Aβ-mediated brain disorder.
5. AβPlaque Disruption
Aggregation of A
β
leads to activation of microglia and astrocytes, and loss of cholinergic neurons,
which is a constant feature of AD [
87
]. Res not only plays an important role in affecting A
β
homeostasis,
but can also inhibit A
β
aggregation from lower molecular weight oligomers into higher molecular
weight oligomers and disrupt preformed A
β
aggregation [
54
,
88
]. One study found that Res could
bind directly to A
β
in different states including monomer and fibril A
β
[
35
]. Additionally, from
indirect inhibitory effect, Res could enhance the binding of A
β
oligomers and TTR which can stabilize
A
β
oligomers structure, preventing plaque aggregation, which provides new perspective into the
protective properties of Res against AD [28,89].
6. Res Analogs in AD Treatment
Res analogs which show better bioavailability, efficacy and stability compared to Res are being
tested for their activity in relation to many degenerative conditions. Some studies showed that
Res derivatives exhibit neuroprotective effects
in vivo
and
in vitro
models [
90
]. Compounds 5d, a3,
5-dimethoxyl derivatives of Res, can cross BBB
in vitro
and are the potent inhibitor of A
β42
aggregation,
disintegration of highly structured with low neurotoxicity [
91
]. Similarly, Piceatannol, a metabolite of
Res found in red wine, protects A
β
-induced neural cell death through affecting the accumulation of
reactive oxygen species (ROS) induced by Res in PC12 cells [
90
]. Pterostilbene is a stilbenoid chemically
related to Res and is a potent modulator of cognition and cellular stress, associated with regulating
peroxisome proliferator-activated receptor alpha (PPAR
α
) protein expression [
92
]. Various Res analogs
and derivatives developed with improved bioavailability possess neuroprotective activities and could
be promising drug candidates in the treatment of AD.
7. Conclusions and Challenges
Recent observations provide strong evidence for the link between A
β
accumulation in the
brain and AD, and the role of A
β
clearance pathway in AD. There is an urgent need to search
for and develop disease-modifying natural products and drugs to treat the major neurodegenerative
disorders [
93
]. In this chapter, we have briefly reviewed the literature on effects of Res, a new rising star
in AD treatment, on A
β
production and A
β
clearance, BBB dysfunction, and A
β
plaque disruption,
supporting an essential role of Res on A
β
homeostasis in AD pathogenesis (Figure 2). In addition to
directly regulating A
β
homeostasis in brain, several
in vitro
studies showed that Res is believed to
afford strong antioxidative and anti-inflammatory properties induced by A
β
, indirectly. Res attenuated
A
β
-induced oxidative stress
in vivo
and
in vitro
[
94
,
95
], suggesting that Res may be of benefit in AD
treatment. Clinical trials indicated that Res seems to be well tolerated with less toxicity and can
penetrate BBB easily. However, low oral bioavailability of Res limited its clinical efficacy because of
rapid excretion and extensive metabolism [
96
]. Numerous clinical trials tried to investigate the effects
of Res on neurodegenerative diseases including AD, although there are many difficulties such as
bioavailability and side effects [
97
]. Addressing these questions will lead to a better understanding of
mechanisms of Res on AD treatment, which will contribute to searching for, developing and designing
new drugs for AD.
Nutrients 2017,9, 1122 8 of 13
Nutrients 2017, 9, 1122 8 of 13
Figure 2. Effect of resveratrol on Aβ homeostasis. Aβ: amyloid-beta; APP: amyloid precursor protein;
ROS: reactive oxygen species; BACE: β-APP cleaving enzyme. ADEs: Aβ-degrading enzymes.
Acknowledgements: We thank the financial support of the Nursing Program for Young Scholars of Heilongjiang
Province of China (No.UNPYSCT-2016116), Natural Science Foundation of China (No. 81303248) and the
Natural Science Foundation of Heilongjiang Province of China (No.H2015028).This research was in part
supported by Item of Scientific Research Fund for Doctor of Qiqihar Medical University (QY2016B-09).
Author contributions: Yongming Jia designed research, searched literatures, wrote the paper and revised the
paper. Na Wang searched literatures. Xue-wei Liu revised the paper.
Conflicts of interest: The authors declare no conflict of interest.
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Figure 2.
Effect of resveratrol on A
β
homeostasis. A
β
: amyloid-beta; APP: amyloid precursor protein;
ROS: reactive oxygen species; BACE: β-APP cleaving enzyme. ADEs: Aβ-degrading enzymes.
Acknowledgments:
We thank the financial support of the Nursing Program for Young Scholars of Heilongjiang
Province of China (No. UNPYSCT-2016116), Natural Science Foundation of China (No. 81303248) and the Natural
Science Foundation of Heilongjiang Province of China (No. H2015028).This research was in part supported by
Item of Scientific Research Fund for Doctor of Qiqihar Medical University (QY2016B-09).
Author Contributions:
Yongming Jia designed research, searched literatures, wrote the paper and revised the
paper. Na Wang searched literatures. Xue-wei Liu revised the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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... Antioxidants such as vitamin C (fruits and vegetables) protect neurons from oxidative stress-induced damage by scavenging for reactive oxidative species (Choudhry et al., 2012). Resveratrol, which is found in berries, grapes and nuts reduces the generation of reactive oxidative species (Bigford and Del Rossi, 2014), and intake has been reported to reduce Aβ deposition, and improve cognitive function (Jia et al., 2017). ...
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Background: As the global population ages, there has been a growing incidence of neurodegenerative diseases such as Alzheimer's. More recently, studies exploring the relationship between dietary patterns and neuroimaging outcomes have received particular attention. This systematic literature review provides a structured overview of the association between dietary and nutrient patterns on neuroimaging outcomes and cognitive markers in middle-aged to older adults. A comprehensive literature search was conducted to find relevant articles published from 1999 to date using the following databases Ovid MEDLINE, Embase, PubMed, Scopus and Web of Science. The inclusion criteria for the articles comprised studies reporting on the association between dietary patterns and neuroimaging outcomes, which includes both specific pathological hallmarks of neurodegenerative diseases such as Aβ and tau and nonspecific markers such as structural MRI and glucose metabolism. The risk of bias was evaluated using the Quality Assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The results were then organized into a summary of results table, collated based on synthesis without meta-analysis. After conducting the search, 6050 records were extracted and screened for eligibility, with 107 eligible for full-text screening and 42 articles ultimately being included in this review. The results of the systematic review indicate that there is some evidence suggesting that healthy dietary and nutrient patterns were associated with neuroimaging measures, indicative of a protective influence on neurodegeneration and brain ageing. Conversely, unhealthy dietary and nutrient patterns showed evidence pointing to decreased brain volumes, poorer cognition and increased Aβ deposition. Future research should focus on sensitive neuroimaging acquisition and analysis methods, to study early neurodegenerative changes and identify critical periods for interventions and prevention. Systematic review registration: PROSPERO registration no, CRD42020194444).
... The aromatic structures of these compounds contribute to the prevention of self-induced Aβ aggregation by disrupting the π stacking of aromatic residues in Aβ aggregate development [63]. In particular, resveratrol (trans-3,4 , 5-trihydroxystilbene), a flavonoid derivative largely found in grapes [64], inhibits Aβ self-aggregation, attenuates Aβ induced toxicity, promotes Aβ clearance, and reduces senile plaques [65]; for these reasons this compound was used as a positive control in Aβ 1-42 aggregation inhibition assays. The results shown in Table 4 reveal that V. effusa and V. clarionifolia were the most potent inhibitors, with inhibition values similar to those of resveratrol. ...
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Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Höck and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC50 between 1.08–12.69 mg/mL) and butyrylcholinesterase (IC50 between 0.0019–1.46 mg/mL). They also inhibited the aggregation of β-amyloid peptide, were able to chelate Fe2+ ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC50: 0.286 mg/mL (0.213–0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD.
... We hypothesized that oAβ42 might be a sensitive biosensor for CSVD. However, no relevant reports have been published and its reliable detection is still a challenge [11][12][13][14]. Transformed after monomer aggregation, oAβ42 has variable subspecies ranging from low (LMW) to high molecular weight (HMW) soluble protofibril (pAβ42); its presence is usually transient and heterogeneous and dynamic equilibrium varies between mAβ42 and oAβ42. ...
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Due to the heterogeneity of amyloid β-42 (Aβ42) species, the potential correlation between plasma oligomeric Aβ42 (oAβ42) and cognitive impairments in cerebral small vessel disease (CSVD) remains unclear. Herein, a sandwich ELISA for the specific detection of Aβ42 oligomers (oAβ42) and total Aβ42 (tAβ42) was developed based on sequence-and conformation-specific antibody pairs for the evaluation of plasma samples from a Chinese CSVD community cohort. After age and gender matching, 3-Tesla magnetic resonance imaging and multidimensional cognitive assessment were conducted in 134 CSVD patients and equal controls. The results showed that plasma tAβ42 and oAβ42 levels were significantly elevated in CSVD patients. By regression analysis, these elevations were correlated with the presence of CSVD and its imaging markers (i.e., white matter hyperintensities). Plasma Aβ42 tests further strengthened the predictive power of vascular risk factors for the presence of CSVD. Relative to tAβ42, oAβ42 showed a closer correlation with memory domains evaluated by neuropsychological tests. In conclusion, this sensitive ELISA protocol facilitated the detection of plasma Aβ42; Aβ42, especially its oligomeric form, can serve as a biosensor for the presence of CSVD and associated cognitive impairments represented by memory domains.
... Mitochondrial function can also be regulated by melatonin [396], methylene blue [397], carotenoids [398], red gingseng [399], and oxaloacetate [400]. Most of these supplements have multiple effects, e.g., inhibition of tau aggregation may be involved in the effects of methylene blue [337,401], red gingseng [402], crocin [403], cinnamaldehyde and epicatechin [404], purpurin [405], and folate [406], and inhibition of Aβ toxicity may be involved in the effects of resveratrol [407], huperzine A (cholinesterase inhibitor and NMDA receptor antagonist) [408,409] and carvacrol (anti-acetylcholinesterase, antioxidant, and neuroprotective properties) [410,411]. ...
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Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.
... In a dose dependent manner, RSV at 5 and 50 µM, but not at 100 µM, prevented microglia activation and promoted and earlier neurogenesis pulse in B1-deficient OHCs, adding confidence to the hypothesis that decreasing neuroinflammation is the trigger to the neurogenesis pulse in the OHC model of TD (Fig. 7). There are evidence that RSV decreases the amyloidogenic cleavage of APP, enhances Aβ clearance and reduces its aggregation [69]. However, it must be taken into account that, in addition to its anti-inflammatory and antioxidant properties, RSV also upregulates Bdnf transcription in the hippocampus [70][71][72][73][74][75]. ...
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Background Thiamine (vitamin B1) is a cofactor for enzymes of central energy metabolism and its deficiency (TD) impairs oxidative phosphorylation, increases oxidative stress, and activates inflammatory processes that can lead to neurodegeneration. Wernicke–Korsakoff syndrome (WKS) is a consequence of chronic TD, which leads to extensive neuronal death, and is associated with neuropathological disorders, including cognitive deficits and amnesia. The hippocampus is one of the brain areas most affected by WKS. B1 replacement may not be enough to prevent the irreversible cognitive deficit associated with WKS. Materials and methods An organotypic hippocampal slice culture (OHC) model was developed to investigate, using immunofluorescence and confocal microscopy and transcriptome analysis, the molecular mechanisms underlying the neurodegeneration associated with TD. The effect of anti-inflammatory pharmacological intervention with resveratrol (RSV) was also assessed in B1-deprived OHCs. Results In OHCs cultured without B1, neuronal density decayed after 5 days and, on the 7th day, the epigenetic markings H3K4me3 and H3K9me3 were altered in mature neurons likely favoring gene transcription. Between the 7th and the 14th day, a pulse of neurogenesis was observed followed by a further massive neuron loss. Transcriptome analysis at day nine disclosed 89 differentially expressed genes in response to B1 deprivation. Genes involved in tryptophan metabolism and lysine degradation KEGG pathways, and those with Gene Ontology (GO) annotations related to the organization of the extracellular matrix, cell adhesion, and positive regulation of synaptic transmission were upregulated. Several genes of the TNF and FoxO signaling pathways and with GO terms related to inflammation were inhibited in response to B1 deprivation. Nsd1 , whose product methylates histone H3 lysine 36, was upregulated and the epigenetic marking H3K36me3, associated with negative regulation of neurogenesis, was increased in neurons. Treating B1-deprived OHCs with RSV promoted an earlier neurogenesis pulse. Conclusion Neuroregeneration occurs in B1-deficient hippocampal tissue during a time window. This phenomenon depends on reducing neuroinflammation and, likely, on metabolic changes, allowing acetyl-CoA synthesis from amino acids to ensure energy supply via oxidative phosphorylation. Thus, neuroinflammation is implicated as a major regulator of hippocampal neurogenesis in TD opening a new search space for treating WKS.
... Resveratrol plays a significant role in boosting non-amyloidogenic cleavage of the amyloid precursor protein, resulting in advancing the clearance of Aβ peptides and decreasing the degradation of neurons (Sergides et al., 2016). Resveratrol (15, 45, and 135 mg/kg) has been reported to block the cholinesterase effect in AD-based animal assays (Jia et al., 2017). A combination study of melatonin (80 mg/kg) with resveratrol (40 mg/kg) showed that melatonin augmented memory deficit effects in novel object recognition task (NORT) and passive avoidance task (PAT) assays of ADbased mouse models. ...
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Central nervous system (CNS) disorders and diseases are expected to rise sharply in the coming years, partly because of the world’s aging population. Medicines for the treatment of the CNS have not been successfully made. Inadequate knowledge about the brain, pharmacokinetic and dynamic errors in preclinical studies, challenges with clinical trial design, complexity and variety of human brain illnesses, and variations in species are some potential scenarios. Neurodegenerative diseases (NDDs) are multifaceted and lack identifiable etiological components, and the drugs developed to treat them did not meet the requirements of those who anticipated treatments. Therefore, there is a great demand for safe and effective natural therapeutic adjuvants. For the treatment of NDDs and other memory-related problems, many herbal and natural items have been used in the Ayurvedic medical system. Anxiety, depression, Parkinson’s, and Alzheimer’s diseases (AD), as well as a plethora of other neuropsychiatric disorders, may benefit from the use of plant and food-derived chemicals that have antidepressant or antiepileptic properties. We have summarized the present level of knowledge about natural products based on topological evidence, bioinformatics analysis, and translational research in this review. We have also highlighted some clinical research or investigation that will help us select natural products for the treatment of neurological conditions. In the present review, we have explored the potential efficacy of phytoconstituents against neurological diseases. Various evidence-based studies and extensive recent investigations have been included, which will help pharmacologists reduce the progression of neuronal disease.
... One of the hallmarks for inducing neuro-inflammation is oxidative stress following by inflammatory cascade which ultimately damage neuronal functioning (memory and cognition). RSV has been extensively investigated for treatment of Aβ-induced neuro-inflammation due to its powerful antioxidant and anti-inflammatory efficacy [50][51][52][53][54]; however, its poor pharmacokinetic profile and vulnerability to photo-oxidation limits its therapeutic viability. Therefore, Frozza et al. [49] encapsulated into NCPs and evaluated for neuroprotective effects. ...
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Owing to their eco-friendliness, natural abundance, cost-effectiveness, and organic nature, numerous phyto- chemicals are being traditionally used for treatment of different diseases. Despite their great potency, clinical translation of phytoconstituents is constrained due to their intrinsic physicochemical properties (i.e., low aqueous solubility, low permeation coefficient, and chemical instability), poor bioavailability, short plasma half- life, and ultimate sub-therapeutic efficacy. To mitigate these shortcomings, nanotechnology has been employed in the past few decades. In this review, we have mainly focused on significance of different nanodelivery systems in improving the physicochemical properties and targeted delivery of anti-inflammatory phytochemicals for treatment of inflammatory diseases. The encapsulation of anti-inflammatory phytochemicals in various nano- delivery systems (phytonanomedicine) has resulted in significant improvement in physicochemical properties, biocompatibility, pharmacokinetic profile, and therapeutic efficacy. Moreover, many recent adaptations including, PEGylation, surface functionalization with targeting ligand(s), and stimuli-responsive behavior of phytonanomedicines have also been pondered to maximize targeted biodistribution, cell uptake efficiency, prolonged localization, and therapeutic efficacy. Convincingly, phytonanomedicines have modernized thera- peutic value of anti-inflammatory phytochemicals for treatment of various inflammatory disorders; however, one of the restrictions to clinical translation of phytonanomedicines is lacking of substantial evidences on their prerequisite safety and efficacy in human which needs further exploration
... Resveratrol and pterostilbene are prospective candidates as anti-aging agents that modulate aging hallmarks, such as oxidative stress and inflammation (Li et al., 2018). The pharmacological activities of resveratrol have been reported in AD models, for example, increasing the clearance of Aβ peptides and reducing Aβ aggregation as well as enhancing neurite outgrowth and synaptogenesis (Jia et al., 2017;Tang et al., 2017). Additionally, pterostilbene exhibited neuroprotective properties by restoring Aβ-induced cognitive dysfunction in a mouse model (Xu et al., 2021). ...
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of amyloid plaques in the brain. The prevention of amyloid-β (Aβ)-induced neuronal toxicity is considered a major target for drug development for AD treatment. Dracaena cochinchinensis (Lour.) S.C. Chen, a Thai folk medicine named “Chan-Daeng,” is a member of the Asparagaceae family. The stemwood of D. cochinchinensis has been traditionally used for its antipyretic, pain relief, and anti-inflammatory effects. The aim of the present study was to determine the pharmacological activities of ethanol and water extracts of D. cochinchinensis stemwood in blocking the Aβ fibril formation, preventing Aβ-mediated cell toxicity, and promoting neuronal differentiation in cultured PC12 cells. The herbal extracts of D. cochinchinensis stemwood prevented the formation of Aβ fibrils and disassembled the aggregated Aβ in a dose-dependent manner. Additionally, they prevented Aβ fibril-mediated cell death. The synergy of the herbal extract with a low dose of the nerve growth factor showed an increase in the protein expression of neurofilaments, that is, NF68, NF160, and NF200. These findings suggest that the extracts of D. cochinchinensis stemwood may be used for AD treatment by targeting Aβ fibril formation and inducing neuron regeneration.
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Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer's disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit Aβ1-42 peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC50 = 3.49 nM) and 43 (IC50 = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC50 = 63 nM). Besides, the selectivity indexes (SI = AChE IC50 / BChE IC50) of 39 (SI = 33) and 43 (SI = 20) were also higher than A3Q12 (SI = 14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective Ki values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Aβ1-42 peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer's disease.
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γ-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ-secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre(+)). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10-fold accumulation of membrane-bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of γ-secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane-bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a- or Aph1bc-secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1-γ-secretase inhibitors should be considered for treatment of Alzheimer's disease.
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Among the low-density lipoprotein receptor (LDLR) family members, the roles of LDLR-related protein 1 (LRP1 or LRP) in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβ) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners. Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apolipoprotein E (apoE), whose gene is the strongest genetic risk factor for AD. Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development. Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified. In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through Aβ-dependent and -independent pathways by reviewing both clinical and preclinical studies. We also discuss potential therapeutic strategies for AD by targeting LRP1.
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Increasing evidence demonstrates that β-amyloid (Aβ) elicits oxidative stress, which contributes to the pathogenesis and disease progression of Alzheimer’s disease (AD). The aims of the present study were to determine and explore the antioxidant nature and potential mechanism of vanillic acid (VA) in Aβ1-42-induced oxidative stress and neuroinflammation mediated cognitive impairment in mice. An intracerebroventricular (i.c.v.) injection of Aβ1-42 into the mouse brain triggered increased reactive oxygen species (ROS) levels, neuroinflammation, synaptic deficits, memory impairment, and neurodegeneration. In contrast, the i.p. (intraperitoneal) administration of VA (30 mg/kg, for 3 weeks) after Aβ1-42-injection enhanced glutathione levels (GSH) and abrogated ROS generation accompanied by an induction of the endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) via the activation of Akt and glycogen synthase kinase 3β (GSK-3β) in the brain mice. Additionally, VA treatment decreased Aβ1-42-induced neuronal apoptosis and neuroinflammation and improved synaptic and cognitive deficits. Moreover, VA was nontoxic to HT22 cells and increased cell viability after Aβ1-42 exposure. To our knowledge, this study is the first to reveal the neuroprotective effect of VA against Aβ1-42-induced neurotoxicity. Our findings demonstrate that VA could potentially serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD.
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Background Treatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. Methods For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. Results Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels. Conclusions Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. Trial registration ClinicalTrials.gov NCT01504854
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Previous in vivo work showed that resveratrol has beneficial effects in the AD pathology, resulting in increased expression of transthyretin (TTR). TTR binds Aβ peptide avoiding its aggregation and toxicity, and is reduced in the CSF and plasma, in AD. Further, resveratrol binds TTR, stabilizing the native TTR tetrameric structure. To further explore the mechanism of neuroprotection conferred by TTR in AD, resveratrol was administrated, in the diet, to 5-8 months old AD transgenic female mice carrying just one copy of the mouse TTR gene, for two months. Effects in brain Aβ burden were evaluated by immunohistochemistry, and in total brain Aβ levels by ELISA, showing a striking decrease in both parameters in treated animals. In addition, total brain LRP1 protein levels were increased in treated animals, although its gene expression was unaltered. To further understand the mechanism(s) underlying such improvement in AD features, we measured TTR plasma levels showing that TTR increased in resveratrol-treated mice, whereas liver TTR gene transcription was not altered. These results strengthen the stability hypothesis, which postulates that TTR is unstable in AD leading to accelerated clearance and lower levels. Therefore, resveratrol which stabilizes the TTR tetramer results in TTR normalized clearance, thus increasing the protein plasma levels. In turn, stabilized TTR binds more strongly to Aβ peptide, avoiding its aggregation. Our results represent a step forward to the understanding of the mechanism underlying TTR protection in AD and highlight the possibility of using TTR stabilization as a therapeutic target in AD.
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Glial cells have a variety of functions in the brain, ranging from immune defence against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer’s disease (AD). One of the most important functions of glial cells in AD is the regulation of Aβ levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of Aβ clearance and degradation. The mechanisms of Aβ degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme (IDE), and the endothelin-converting enzymes, able to hydrolyse Aβ at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in Aβ elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of Aβ alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, α2macroglobulin, and α1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing Aβ, in many cases via a number of receptors that are expressed on their surface. In this review we examine all of these mechanisms, providing an update on the latest research in this field.
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