Resveratrol and Amyloid-Beta: Mechanistic Insights

Abstract

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.

Full text

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 [16–18]. 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 [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.
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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