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Consumption of Grape Seed Extract Prevents Amyloid-β Deposition and Attenuates Inflammation in Brain of an Alzheimer’s Disease Mouse

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Polyphenols extracted from grape seeds are able to inhibit amyloid-beta (Abeta) aggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We aimed to investigate the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in Alzheimer's disease (AD) mice. APP(Swe)/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid (49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and proanthocyanidins (436.6 mg catechin equivalents/g). Long-term feeding of GSE diet was well tolerated without fatality, behavioural abnormality, changes in food consumption, body weight or liver function. The Abeta levels in the brain and serum of the mice fed with GSE were reduced by 33% and 44%, respectively, compared with the Alzheimer's mice fed with the control diet. Amyloid plaques and microgliosis in the brain of Alzheimer's mice fed with GSE were also reduced by 49% and 70%, respectively. Curcumin also significantly reduced brain Abeta burden and microglia activation. Conclusively, polyphenol-rich GSE prevents the Abeta deposition and attenuates the inflammation in the brain of a transgenic mouse model, and this thus is promising in delaying development of AD.
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Consumption of Grape Seed Extract Prevents
Amyloid-b Deposition and Attenuates Inflammation in Brain
of an Alzheimer’s Disease Mouse
Yan-Jiang Wang Æ Philip Thomas Æ Jin-Hua Zhong Æ
Fang-Fang Bi Æ Shantha Kosaraju Æ Anthony Pollard Æ
Michael Fenech Æ Xin-Fu Zhou
Received: 22 July 2008 / Revised: 19 September 2008 / Accepted: 19 September 2008 / Published online: 10 February 2009
Ó Springer Science+Business Media, LLC 2009
Abstract Polyphenols extracted from grape seeds are
able to inhibit amyloid-beta (Ab) aggregation, reduce Ab
production and protect against Ab neurotoxicity in vitro.
We aimed to investigate the therapeutic effects of a poly-
phenol-rich grape seed extract (GSE) in Alzheimer’s
disease (AD) mice. APP
Swe
/PS1dE9 transgenic mice were
fed with normal AIN-93G diet (control diet), AIN-93G diet
with 0.07% curcumin or diet with 2% GSE beginning at
3 months of age for 9 months. Total phenolic content of
GSE was 592.5 mg/g dry weight, including gallic acid
(49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and
proanthocyanidins (436.6 mg catechin equivalents/g).
Long-term feeding of GSE diet was well tolerated without
fatality, behavioural abnormality, changes in food con-
sumption, body weight or liver function. The Ab levels in
the brain and serum of the mice fed with GSE were reduced
by 33% and 44%, respectively, compared with the Alz-
heimer’s mice fed with the control diet. Amyloid plaques
and microgliosis in the brain of Alzheimer’s mice fed with
GSE were also reduced by 49% and 70%, respectively.
Curcumin also significantly reduced brain Ab burden and
microglia activation. Conclusively, polyphenol-rich GSE
prevents the Ab deposition and attenuates the inflammation
in the brain of a transgenic mouse model, and this thus is
promising in delaying development of AD.
Keywords Alzheimer’s disease Polyphenols
Grape seed extract Curcumin Amyloid-beta
Microglia Inflammation
Introduction
Alzheimer’s disease (AD) is the most common form of
senile dementia occurring in later life and is a major cause
of disability and death in the elderly (World Health
Organization 2003). With the world population ageing, it is
estimated that the number of people affected with AD will
double every 20 years from today’s estimate of 26.6 mil-
lion to 106.8 million by 2050 (Brookmeyer et al.2007).
However, no strong disease-modifying treatment or pre-
ventative measure is currently available (Citron 2004).
AD is characterized neuropathologically by deposits of
amyloid-beta peptides (Ab), neurofibrillary tangles, reac-
tive microgliosis and astrogliosis, cerebral amyloid
angiopathy and neuronal loss that result in the progressive
deterioration of cognition and memory (see Thomas and
Fenech 2007, review). According to the amyloid hypoth-
esis, the accumulation of Ab in the brain is the primary
factor driving AD pathogenesis (Hardy and Selkoe 2002).
The authors Y.-J. Wang and P. Thomas contributed equally to this
work.
Y.-J. Wang J.-H. Zhong F.-F. Bi A. Pollard
X.-F. Zhou (&)
Department of Human Physiology and Centre for Neuroscience,
Flinders University, GPO Box 2100, Adelaide, SA, Australia
e-mail: xin-fu.zhou@flinders.edu.au
P. Thomas M. Fenech (&)
Australian Commonwealth Scientific and Research Organization
(CSIRO) Human Nutrition, P.O. Box 10041, Adelaide BC,
Adelaide, SA, Australia
e-mail: Michael.Fenech@csiro.au
S. Kosaraju
CSIRO Food Science Australia, 671 Snydes Rd,
Private Bag 16, Werribee, VIC 3030, Australia
Y.-J. Wang
Department of Neurology, Chongqing Daping Hospital,
Third Military Medical University, Chongqing 400042, China
123
Neurotox Res (2009) 15:3–14
DOI 10.1007/s12640-009-9000-x
It has been suggested that neuroinflammation may signifi-
cantly contribute to disease progression and chronicity of
AD (Heneka and O’Banion 2007). Therefore, clearance of
Ab from the brain and anti-inflammation represent poten-
tial important strategies that may be used to prevent and
treat the disease (Citron 2004; Wang et al. 2006b).
Epidemiological studies have shown that consumption of
diets rich in anti-inflammatory agents, such as those found
in fruits and vegetables, or anti-inflammation drugs, may
lower the risk of developing age-related neurodegenerative
diseases such as Parkinson’s disease and AD (Lau et al.
2005; Barberger-Gateau et al. 2007; McGeer and McGeer
2007). Polyphenols from grape seeds extract (GSE) have
been suggested to be able to inhibit Ab aggregation, reduce
Ab production, protect against Ab neurotoxicity and
attenuate oxidative stress in vitro (Bastianetto et al. 2000;
Jang and Surh 2003; Ono et al. 2003, 2005; Savaskan et al.
2003; Li et al. 2004; Marambaud et al. 2005; Mancuso et al.
2007; Riviere et al. 2007). GSE has been widely used as
food additives in order to benefit health and chronic illness
due to its anti-oxidation effects (for review, see Shi
et al.2003). However, whether polyphenols from grape
seeds can prevent or slow down the pathogenesis of the
disease or reduce brain pathology in AD patients or animal
models is not clear. In the present study, we investigated the
effects of polyphenol-rich GSE on Ab deposition and
inflammation in a transgenic AD mouse model.
Materials and Methods
Transgenic Mouse Model
Approval for this study was obtained from CSIRO Human
Nutrition and Flinders University Animal Ethics commit-
tees. APP
Swe
/PS1dE9 transgenic mice were provided by
Jackson Laboratory, USA. These mice were constructed on
a C57BL/6 background and bear a chimeric mouse/human
(Mo/Hu) APP695 with mutations linked to familial AD
(KM 593/594 NL) and human PS1 carrying the exon-9-
deleted variant associated with familial AD (PS1dE9) in
one locus under control of a brain- and neuron-specific
murine Thy-1 promoter element (Jankowsky et al.2001).
Genotyping of mice was performed by PCR following the
supplier’s instructions. Mice were maintained on ad libitum
food and water with a 12-h light/dark cycle.
The 3-month-old APP
Swe
/PS1dE9 transgenic mice were
randomly assigned to a polyphenol group (N = 12, fed
with polyphenol diet), curcumin group (N = 12, fed with
curcumin diet) and normal diet group (N = 12, fed with
normal diet). The age- and sex-matched wild-type litter-
mates were used as a normal control (N = 20, fed with
normal diet). All animal husbandry procedures performed
were approved by the Flinders University and CSIRO
Human Nutrition Animal Welfare Committees in accor-
dance with NHMRC Australian guidelines in Australia.
HPLC Analysis of Polyphenols in GSE
GSE (Vinlife N05010) was purchased from Tarac Tech-
nologies P.L. and was characterized by high performance
liquid chromatography (HPLC) analysis without any fur-
ther extraction process. GSE, dissolved in 80% methanol
acidified with 0.1% HCl to obtain final concentration of
2.0 mg/ml, was injected (10 ll) into the HPLC column for
the analysis of polyphenolic compounds. HPLC analysis
was carried out according to methods described previously
(Kammerer et al.2004). Analytical HPLC was run at 25°C
and monitored at 280 nm (hydroxybenzoic acids and
flavanols), 320 nm (hydroxycinnamic acids, stilbenes) and
370 nm (flavonols).
Diets
Before experiments, all animals were fed with commercial
standard diet pellets (Gordon’s Specialty Stock Feeds Pty
Ltd., NSW, Australia). All experimental diets were pre-
pared by Specialty Feeds, Glen Forrest, Western Australia.
The Control diet was the standard AIN-93G rodent diet
(Reeves 1997) consisting of 39.7% corn starch, 20% casein
(vitamin free), 13.2% dextrin, 10% sucrose, 7% soybean
oil, 5% powdered cellulose, 3.5% AIN-93G mineral mix,
1% AIN-93G vitamin mix, 0.3%
L-cysteine, 0.25% choline
bitartrate, 0.001% t-butylhydroquinone and 5% maize
starch. Curcumin diet consisted of the AIN-93G diet with
the exception that it contained 4.93% maize starch and
0.07% curcumin (Sigma, Cat No.: C1386, USA). GSE diet
consisted of the AIN-93G diet with the exception that it
contained 3% maize starch and 2% GSE. The dosage of
curcumin and GSE was based on previous reports indi-
cating lack of toxicity and in the case of curcumin
preventive effects against AD in a mouse model
(Yamakoshi et al. 2002; Deshane et al. 2004; Yang et al.
2005). Sufficient diet was prepared for the duration of the
study and housed at the Flinders Medical Centre animal
holding facility. The animals were fed with the above diets
for 9 months starting from when they were 3 months old,
at which time no Ab deposition was formed in the brain of
the animal (Garcia-Alloza et al. 2006). Food consumption
and animal body weight were monitored every 3 months
throughout the study.
Tissue Sampling
Animals were sacrificed by overdosing with chloral hydrate
(1.5 g/kg). Blood was sampled from the right atrium of the
4 Neurotox Res (2009) 15:3–14
123
heart, followed by intracardial perfusion with 100 ml of
0.1% NaNO
2
in phosphate buffer. Brains were sampled and
weighed on a digital electronic balance with a readability
of 1 mg (BX-420H, Shimadzu Scientific Instruments,
USA). Left brain hemisphere for histological analysis was
fixed in 4% paraformaldehyde (pH 7.4) for 24 h and
incubated for 24 h in 30% sucrose for subsequent cryo-
protection. Coronal sections of the brain at 35-lm
thickness were collected with a cryosectioning microtome
and stored at 4°C in PBS containing 0.1% sodium azide
until use. Right brain hemisphere was snap frozen in liquid
nitrogen and stored at -80°C for future biochemical
analysis.
AD-type Pathology and Quantitative Image Analysis
The staining for brain total Ab, microgliosis, astrogliosis
and microhaemorrhage was processed as described previ-
ously (Wang et al. 2009). Briefly, three series of six equally
spaced tissue sections (*200 lm apart) spanning the
hippocampus were randomly selected and stained using
free-floating immunohistochemistry for total Ab (Biotin-
conjugated mouse anti-Ab antibody 6E10, Serotec, USA;
1:1000 dilution), activated microglia (rat monoclonal anti-
CD45, Chemicon, USA; 1:2000 dilution) and astrocyte
(rabbit polyclonal anti-glial fibrillary acidic protein, Dako,
Denmark; 1:1000 dilution), respectively. Sections were
incubated overnight with primary antibodies at 4°C, further
developed with biotinylated secondary antibodies and the
ABC kit (Vector Lab, Burlingame, CA) using diam-
inobenzidine and glucose oxidase as substrates. Quantifi-
cation of total Ab deposit, microgliosis and astrogliosis
were performed on images acquired with a digital camera
and analysed with NIH Image J.
Images were collected at 49 magnification using con-
stant bulb temperature and exposure, with all images
acquired in the same session. The area of neocortex and
hippocampus was selected for automatic quantification of
Ab, microglia and astrocyte immunostaining, yielding the
area fraction of the total positive staining against the area
of tissue analysed. The average of the individual mea-
surements was used to calculate group means and standard
errors.
A series of six equally spaced tissue sections (*1mm
apart) spanning the entire brain was mounted and stained
for haemosiderin using 2% potassium ferrocyanide in 2%
HCl for 15 min, followed by a counterstain in a 1% Neutral
Red solution for 10 min at room temperature. Micro-
haemorrhage events in the form of the number of Prussian
blue-positive profiles were counted in the brains of each
mouse on all sections, and the average number of haemo-
siderin deposits was calculated per each brain hemisphere.
All image analyses were processed in a blind manner.
Quantification of Ab Peptide Levels in the Mouse Brain
and Plasma by ELISA
ELISA analysis of the brain Ab was processed as described
previously (Wang et al. 2009). Briefly, frozen brain was
homogenized and sonicated in water containing 2% sodium
dodecyl sulphate (SDS) and protease inhibitors (Boehrin-
ger Mannheim, Germany). Homogenates were centrifuged
at 100,000g for 1 h at 4°C, and the resultant supernatant
was collected, representing the SDS-soluble fraction (Ab-
SDS). The resultant pellet was then extracted in 70% for-
mic acid, centrifuged, and the resultant supernatant was
collected, representing the SDS-insoluble fraction (Ab-
FA). Before ELISA assay, SDS extracts were diluted 1:50
and formic acid extracts were neutralized by 1:20 dilution
into 1 M Tris phosphate buffer, pH 11, and then diluted
1:20 in sample buffer. Concentration of Ab40 and of Ab42
in brain extract and plasma were quantitatively measured
by ELISA (catalogue nos. 8940 and 8942; Signet Labora-
tories, Dedham, MA) according to manufacturer’s
instructions. Using the wet weight of brain tissue in the
original homogenate, the final values of brain A
b were
expressed as picomoles per gram wet weight of brain.
Quantification of TNFa, IL-1b and IFN-c in the Mouse
Plasma by ELISA
TNFa, IL-1b and IFN-c in the plasma of mice were
measured using ELISA kits (Cat No. 88-7342, 88-
7913, 88-7914, eBioscience, USA) as per manufacturer’s
instructions.
Assessment of Toxicity of Polyphenol from Grape
Seeds
Total bilirubin, alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) were analyzed using
commercial enzyme assays according to the manufac-
turer’s instructions (Roche Diagnostics, GmbH, d-68298
Mannheim).
Statistical Analysis
The data in the text and figures are expressed as mean ±
SEM, unless otherwise stated. Inter-group comparisons
were assayed using one-way ANOVA and post hoc for
testing the significance of values. The Spearman correlation
coefficient was used to analyze the correlation of brain
weight with Ab level, microglia activation and astrocytosis
in the brain and the correlation between brain Ab level and
serum Ab level. P values less than 0.05 were considered as
statistically different. All the analyses were performed using
SPSS for Windows version 13.0 (SPSS Inc.).
Neurotox Res (2009) 15:3–14 5
123
Results
Chemical Analysis of Polyphenols in GSE
HPLC analysis detected compounds in GSE only at
280 nm (Fig. 1). At this wavelength phenolic acids (gallic
acid) and flavanols (catechins) were detected. The level of
proanthocyanidins was calculated as a difference between
the total peak area at 280 nm and the area of individual
peaks that represent the monomers.
Through spectral characteristics and comparison with
standards we detected three main compounds, which were
gallic acid (49 mg/g DW), catechin (41 mg/g DW) and
epicatechin (66 mg/g DW). The concentration of proanth-
ocyanidins was 436.6 mg catechin Eq./g DW. The total
polyphenolic content was 592.5 mg/g DW. A similar total
phenolic content was obtained when analysed by the Folin-
Ciocalteu method (data not shown).
GSE is Well Tolerated in APP
Swe
/PS1dE9 Transgenic
Mice
The overall goal of the present study was to test the
hypothesis that polyphenols from grape seeds may prevent
AD-type Ab-associated pathology. The feed of the poly-
phenols and curcumin diet was from 3 months of age,
when Ab deposition had not yet formed in the brain, to
12 months of age. In APP
Swe
/PS1dE9 transgenic mice, Ab
deposition begins at 4 months of age and becomes obvious
at 9 months of age (Garcia-Alloza et al. 2006; Wang et al.
2006c).
The mean daily food consumption of the mice was
0.11–0.14 g per gram body weight, the corresponding daily
polyphenol consumption was 1.2–1.7 mg per gram body
weight and daily curcumin consumption was 77–98 lg per
gram body weight. The equivalent consumption in a 60 kg
human is about 5.9 g per day for polyphenol and 0.35 g per
day for curcumin, as derived using FDA criteria for con-
verting drug equivalent dosages across species, based on
body surface area [human equivalent dose in mg/kg =
animal dose in mg/kg 9 (animal weight in kg/human
weight in kg)
0.33
] (Food and Drug Administration 2003).
During the period of the study, no animal death occurred
and no behavioural abnormality was observed. We found
that the long-term daily consumption for 9 months in
APP
Swe
/PS1dE9 transgenic mice, delivered in the food, did
not significantly influence animal body weight (Fig. 2a)
and daily food consumption (Fig. 2b).
It is important to note that the chronic consumption of
polyphenols and curcumin did not cause liver function
damage, as reflected by the normal serum levels of bili-
rubin, aminotransferase (AST) and alanine aminotrans-
ferase aspartate (ALT) (Fig. 2c), and bilirubin which was
detected at a very low level (\1 lmol/l) in serum of all
animals (data not shown).
GSE Reduces Brain and Serum Ab Levels and Prevents
Ab Deposition in APP
Swe
/PS1dE9 Transgenic Mice
After 9 months feeding on different diets, Ab in SDS
fraction (Ab-SDS) and in formic acid fraction (Ab-FA)
were quantified utilizing a sandwich ELISA. Ab-SDS
represents the soluble forms of Ab, while Ab-FA repre-
sents the insoluble forms of Ab. The total Ab level from
individual animals was calculated by the sum of total SDS-
soluble Ab (SDS-soluble Ab42 and Ab40) and total FA
soluble Ab (FA soluble Ab42 and Ab40).
Compared with transgenic mice consuming Control diet,
there was a significant reduction in the total brain Ab burden
in mice consuming a GSE diet (P \ 0.001) or Curcumin diet
(P = 0.01) (ANOVA, F = 10.762, P \ 0.001, Fig. 3a).
GSE diet consumption led to a 33% reduction in brain Ab
burden, while Curcumin diet consumption resulted in a 22%
reduction. Consistently, inter-group comparisons of SDS-
Ab and FA-Ab,Ab40 and Ab42 are essentially the same as
those of total Ab (Fig. 3b, c).
GSE or Curcumin diet consumption also reduced the Ab
concentrations in the serum (ANOVA, F = 10.004,
P \ 0.001, Fig. 3d). The total Ab concentration in serum
correlated significantly and positively with brain total Ab
burden (Pearson r = 0.348, P = 0.021), suggesting the
Fig. 1 HPLC profile of phenolic compounds in GSE. Analytical
HPLC was run at 25°C and monitored at 280 nm (hydroxybenzoic
acids and flavanols), 320 nm (hydroxycinnamic acids, stilbenes) and
370 nm (flavonols). Compounds were detected at 280 nm including
phenolic acids (gallic acid) and flavanols (catechins). The level of
proanthocyanidins was calculated as a difference between the total
peak area at 280 nm and the area of individual peaks that represent
the monomers. The mobile phase consisted of 2% acetic acid in water
(solvent A) and 1.0% acetic acid in water and acetonitrile (50:50 v/v,
solvent B). The flow rate was 1 ml min
-1
. The following gradient
programme was used: from 10% to 24% solvent B (20 min), from
24% to 30% B (20 min), from 30% to 55% B (20 min), from 55% to
100% B (15 min), 100% B isocratic (8 min), from 100% to 10% B
(2 min). The total run time was 85 min
6 Neurotox Res (2009) 15:3–14
123
potential value of serum Ab concentration monitoring to
reflect brain Ab burden during the course of Alzheimer’s
dietary prevention studies with polyphenols and curcumin.
Ab plaques were observed primarily in the neocortical
and hippocampal areas of the brain. Quantitative histology
analysis using ANOVA also generated similar results
(F = 6.873, P = 0.004). Compared with Control diet
consumption (Fig. 4a), consumption of GSE (P = 0.002)
or Curcumin (P = 0.015) diets reduced the Ab deposition
in the neocortex and hippocampus (Fig. 4b, c). Similar to
the brain Ab levels determined by Ab ELISA, the total Ab
plaque burden determined by immunohistochemistry was
reduced by 45% in the GSE diet group and 33% in the
Curcumin diet group. These data suggest polyphenols from
grape seeds are effective in reducing Ab burden and pre-
venting Ab deposition in the brain.
GSE Prevents AD-type Neuropathology
in APP
Swe
/PS1dE9 Transgenic Mice
Microgliosis and astrogliosis were observed primarily in
the neocortical and hippocampal areas of the brain. We
examined the area fraction of CD45? microglia and
GFAP? astrocytes in neocortical and hippocampal regions.
No obvious microgliosis was observed in brains of wild-
type littermates (Fig. 5a), while APP
Swe
/PS1dE9 transgenic
mice showed obvious microgliosis (Fig. 5b). Statistical
analysis using ANOVA (F = 10.260, P \ 0.001)) showed
that, compared with transgenic mice fed with Control diet,
the mice fed with GSE had a significant lower level of
microgliosis (0.51 ± 0.08 vs. 1.72 ± 0.34, P \ 0.001),
similarly so were the mice fed with curcumin (1.11 ± 0.16
vs. 1.72 ± 0.34, P = 0.032) (Fig. 5c–e).
Wild-type littermates fed with control diet had obvi-
ous astrogliosis (Fig. 6a), which, however, was signifi-
cantly lower than that in APP
Swe
/PS1dE9 transgenic mice
(Fig. 6b). There was no significant difference in astrogliosis
among the groups of transgenic mice fed with Control,
Curcumin and GSE diets (ANOVA, F = 2.540, P = 0.097,
Fig. 6b–e).
Characteristic blue haemosiderin-positive profiles were
observed primarily in the neocortical, leptomeningeal,
hippocampal and thalamic areas of the brain (Fig. 7a). The
microhaemorrhage was detected at a rate of 44.0 ± 14.6 per
hemibrain in transgenic mice fed with normal diet, which
was higher than in wild-type littermates (7.76 ± 1.07 per
hemibrain, P = 0.006). Non-significant lower rates of
microhaemorrhage were observed in mice fed with GSE
(29.0 ± 6.2 per hemibrain, P = 0.270) or Curcumin
(32.1 ± 8.4 per hemibrain, P = 0.383) diets when com-
pared with transgenic mice fed with Control diet (ANOVA,
F = 0.599, P = 0.557, Fig. 7b).
Plasma Levels of Inflammatory Cytokines After GSE
Consumption
Activated microglia and microphages secrete cytokines
such as IL-1b, TNF-a and IFN-c. This is a major pathologic
Fig. 2 Polyphenols from grape seeds are well tolerated in APP
Swe
/
PS1dE9 transgenic mice. APP
Swe
/PS1dE9 transgenic mice were fed
Control, Curcumin or GSE diets for 9 months from 3 months of age.
In parallel control studies, gender- and age-matched wild-type
littermates were fed with Control diet. a Body weight was measured
at 3, 6, 9 and 12 months of age. b Food intake was monitored at 3, 6,
9 and 12 months of age, and was calculated as food intake (gram) per
gram body weight per day. c Serum indices of liver functional status
such as AST and ALT. Points and bar graphs represent group mean
(±SEM)
Neurotox Res (2009) 15:3–14 7
123
event in the progression of inflammatory cascades within
the AD brain. We measured the levels of IL-1b, TNF-a and
IFN-c in the plasma. In general, cytokines were detected
but at very low levels which were at the lower range of the
sensitivity of the ELISA kit used (8–15 pg/ml). Levels of
IL-1b and TNF-a tended to be higher in transgenic mice
Fig. 3 Effects of polyphenol
consumption on Ab levels in the
brain and serum of APP
Swe
/
PS1dE9 transgenic mice. Ab
peptide concentration in the
brain and serum of each animal
was measured using ELISA. a
Comparison of total Ab,Ab in
SDS fraction (Ab-SDS) and Ab
in formic acid fraction (Ab-FA)
among groups. b Comparison of
total Ab40, Ab40-SDS and
Ab40-FA. c Comparison of total
Ab42, Ab42-SDS and Ab42-
FA. d Comparison of total Ab,
Ab40 and Ab42 in serum. * and
** denote P \ 0.05 or P \ 0.01
versus APP
Swe
/PS1dE9
transgenic mice fed with
Control diet
Fig. 4 Effects of polyphenol consumption on Ab plaque burden in
the brain of APP
Swe
/PS1dE9 transgenic mice. A series of six equally
spaced tissue sections (*200 lm apart) spanning the hippocampus
were stained using free-floating immunohistochemistry for Ab plaque
(anti-Ab antibody 6E10, Serotec) and developed with DAB. The area
of neocortex and hippocampus was selected for automatic quantifi-
cation of Ab plaque immunostaining with ImageJ, yielding the area
fraction of the total positive staining against the area of tissue
analysed. The average of the individual measurements was used to
calculate group means and standard errors. ac Ab plaques in
hippocampus and neocortex of APP
Swe
/PS1dE9 transgenic mice fed
with Control, Curcumin or GSE diets. d Comparison of Ab plaque
area fraction in neocortex and hippocampus among groups. * and **
denote P \ 0.05 or P \ 0.01 versus APP
Swe
/PS1dE9 transgenic
mice fed with Control diet. Scale bar = 0.5 mm. Original magnifi-
cation, 49
8 Neurotox Res (2009) 15:3–14
123
than in wild-type littermates, but the difference between
groups did not reach statistical significance (ANOVA,
IL-1b, F = 1.881, P = 0.141; TNF-a, F = 1.178, P =
0.325, Fig. 8). The level of IFN-c was higher in transgenic
AD mice fed with Control diet (28.7 ± 10.3 pg/ml) than in
their wild-type littermates (14.9 ± 1.2 pg/ml, P = 0.008)
on the same diet. Compared with Control diet consump-
tion, GSE (19.0 ± 2.0 pg/ml vs. 28.7 ± 10.3 pg/ml, P =
0.336) and Curcumin (15.1 ± 2.0 pg/ml vs. 28.7 ±
10.3 pg/ml, P = 0.021) diet consumption decreased the
IFN-c level in the plasma of APP
Swe
/PS1dE9 transgenic
mice (ANOVA, F = 2.755, P = 0.049, Fig. 8).
Discussion
Both genetics and environment determine the development
of many chronic diseases including AD. The genetic
mutations of APP and presenilin genes only attribute to a
relatively small number (\5%) of the total number of AD
Fig. 5 Effects of polyphenol consumption on microgliosis in the
brain. A series of six equally spaced tissue sections (*200 lm apart)
spanning the hippocampus were stained using free-floating immuno-
histochemistry for activated microglia (rat monoclonal anti-CD45,
Millipore) and developed with DAB. The area of neocortex and
hippocampus was selected for automatic quantification of activated
microglia immunostaining with ImageJ, yielding the area fraction of
the total positive staining against the area of tissue analysed. The
average of the individual measurements was used to calculate group
means and standard errors. a No obvious microgliosis was observed
in the brain of wild-type littermates fed with Control diet. bd
Microgliosis in hippocampus and neocortex of APP
Swe
/PS1dE9
transgenic mice fed with Control, Curcumin or GSE diets. e
Comparison of CD45 area fraction in neocortex and hippocampus
among groups. * and ** denote P \ 0.05 or P \ 0.01 versus wild-
type littermate fed with normal diet,
#
and
##
denote P \ 0.05 or
P \ 0.01 versus APP
Swe
/PS1dE9 transgenic mice fed with Control
diet. Scale bar = 0.5 mm. Original magnification, 49
Neurotox Res (2009) 15:3–14 9
123
Fig. 6 Effects of polyphenol
consumption on astrogliosis in
the brain. A series of six equally
spaced tissue sections
(*200 lm apart) spanning the
hippocampus were stained using
free-floating
immunohistochemistry for
astrocyte (rabbit polyclonal
anti-glial fibrillary acidic
protein, Dako) and developed
with DAB. The area of
neocortex and hippocampus was
selected for automatic
quantification of astrogliosis
immunostaining with ImageJ,
yielding the area fraction of the
total positive staining against
the area of tissue analysed. The
average of the individual
measurements was used to
calculate group means and
standard errors. a Astrogliosis in
hippocampus and neocortex of
wild-type littermates fed with
Control diet. bd Astrogliosis in
hippocampus and neocortex of
APP
Swe
/PS1dE9 transgenic
mice fed with Control,
Curcumin or GSE diets.e
Comparison of GFAP area
fraction in neocortex and
hippocampus among groups. *
and ** denote P \ 0.05 or
P \ 0.01 versus wild-type
littermate fed with Control diet.
Scale bar = 0.5 mm. Original
magnification, 49
Fig. 7 Effects of GSE and curcumin consumption on microhaemor-
rhage profiles in the brain. A series of six equally spaced tissue
sections (*1 mm apart) spanning the entire brain was mounted and
stained for haemosiderin using 2% potassium ferrocyanide in 2%
hydrochloric acid, followed by a counterstain in a 1% Neutral Red
solution. Microhaemorrhage events in the form of the number of
Prussian blue-positive profiles were counted, and the average number
and standard error of haemosiderin deposits was calculated per each
brain hemisphere. a An example of microhaemorrhage profile (solid
arrow) observed in hippocampus. b Comparison of microhaemor-
rhage profiles per each brain hemisphere among groups. * and **
denote P \ 0.05 or P \ 0.01 versus wild-type littermate fed with
Control diet. Scale bar = 50 lm. Original magnification, 409
10 Neurotox Res (2009) 15:3–14
123
patients (familial cases), whereas the majority of AD
patients are likely due to environmental factors and other
genetic factors affecting Ab clearance (Hardy and Selkoe
2002). Major environmental factors are likely to include
excess or deficiency of dietary constituents consumed on a
regular basis which have bioactivity in relevant pathways.
Our understanding of how food and drink can potentially
influence the development of AD will help to develop and
implement treatments that may aid in combating this
devastating disease.
In the present study, we report that polyphenols-rich
GSE fed for 9 months as a food additive dramatically could
prevent the AD development in a genetic mouse model.
We found that the chronic consumption of polyphenols
extracted from grape seeds was well tolerated, effectively
reduced the Ab burden in the brain and blood, prevented
the Ab deposition and attenuated the microgliosis.
Ab accumulation and deposition in the brain is one of
the histopathological hallmarks of AD. Our study clearly
demonstrated that the polyphenols in GSE, when fed to a
transgenic mouse model for 9 months, reduced the total
brain amyloid burden by 33–45%, depending on the anal-
ysis methods used. Ab40 and Ab42 are the major forms of
amyloid-beta peptides in the brain. Ab42 is much more
prone to aggregation and more toxic to neurons than Ab40
(Jarrett et al. 1993; El-Agnaf et al. 2000). In the present
study, it appears that GSE reduced Ab40 slightly more than
Ab42, which is consistent with a recent study (Wang et al.
2008). However, the mechanism of this differential effect
is not known. We used curcumin as a positive control at a
dietary concentration known to reduce the brain amyloid
burden (Yang et al. 2005). Our data indicate that the
polyphenols-rich GSE are comparable to curcumin in the
reduction of brain and plasma amyloid burden. As there are
a number of polyphenols in GSE, it is not known which
polyphenol plays a major role in these events. However, we
assume that the combination of all polyphenols could be
important in achieving these desirable effects. The role
these polyphenols play in the reduction of the amyloid
burden is not known. Recently, other known polyphenols
have been shown to be able to influence Ab metabolism
and protect against Ab neurotoxicity. Curcumin, a phenolic
yellow pigment found in turmeric and a spice used exten-
sively in Asian Indian food, can directly bind small Ab
species to block the formation of oligomer and fibril as well
as to disaggregate Ab aggregates in vitro, and can reduce
amyloid levels and plaque burden in aged transgenic AD
mice when administered peripherally (Lim et al. 2001;
Yang et al.2005). The consumption of the green tea poly-
phenol epigallocatechin-3-gallate has also been shown to
reduce the overproduction of Ab in vitro (Levites et al.
2003) and in the transgenic AD mouse brain (Rezai-Zadeh
et al. 2005) by promoting the non-amyloidogenic alpha-
secretase proteolytic pathway, and reduce the generation of
holo-APP and Ab presumably via iron chelating effects of
the polyphenol in vitro (Reznichenko et al. 2006). In the
present study, holo-APP expression did not change after
chronic consumption of GSE or curcumin (data not
shown). Wine is rich in polyphenols, and wine consump-
tion is related to a lower risk for Alzheimer’s disease in
epidemiological studies (Orgogozo et al. 1997; Lindsay
et al.2002; Letenneur 2004). This has been confirmed in an
animal study showing that wine consumption is effective in
preventing Alzheimer’s disease, also by increasing the non-
amyloidogenic alpha-secretase activity (Wang et al.2006a).
It is known that grape-derived polyphenols inhibit Ab
aggregation, reduce Ab production, degrade intracellular
Ab, protect against Ab neurotoxicity and attenuate oxida-
tive stress in vitro (Bastianetto et al. 2000; Jang and Surh
2003; Ono et al. 2003, 2005; Savaskan et al. 2003; Li et al.
2004; Marambaud et al. 2005; Mancuso et al. 2007; Riviere
et al. 2007). It is likely that the polyphenols from GSE act
on similar multiple pathways to reduce the brain amyloid
burden. A reducing effect was observed preferentially on
the insoluble fraction of both Ab40 and Ab42 in our study,
suggesting that GSE and curcumin probably affect the
assembly or disruption of preformed fibrils and Ab
aggregation (Wang et al. 2008). However, chronic con-
sumption of GSE-derived polyphenols did not change the
activities of Ab generating and degradating enzymes
(Wang et al. 2008). Thus, mechanisms of GSE in modu-
lating Ab metabolism need further investigation and novel
pathways need to be explored.
Inflammation is another hallmark of AD. There is
mounting evidence that chronic inflammatory processes
play a fundamental role in the progression of
Fig. 8 Effects of curcumin and GSE consumption on plasma levels
of TNFa, IL-1b and IFN-c. Plasma levels of TNFa, IL-1b and IFN-c
were measured using ELISA kits (eBioscience). ** denotes P \ 0.01
versus wild-type littermate fed with normal diet,
#
denotes P \ 0.05
versus APP
Swe
/PS1dE9 transgenic mice fed with Control diet
Neurotox Res (2009) 15:3–14 11
123
neuropathological changes in the AD brain (Akiyama et al.
2000; von Bernhardi 2007). The major players involved in
the inflammatory process in AD are thought to be
microglia. Cytokine production by activated microglia,
such as IL-1b, TNF-a and IFN-c, is a key pathologic event
in the progression of inflammatory cascades (Jekabsone
et al. 2006; Meme et al. 2006; Yamamoto et al. 2007). In
the present study, chronic polyphenol consumption effec-
tively alleviated microgliosis. The serum levels of IL-1b,
TNF-a and IFN-c in transgenic mice were higher than in
wild-type littermates. This is consistent with the findings
from AD patients that IL-1b, TNF-a and IFN-c are up-
regulated (Fillit et al. 1991; Blum-Degen et al. 1995; Sol-
erte et al. 2000). Polyphenol and curcumin consumption
tend to decrease plasma levels of IFN-c. However, we did
not observe a difference in serum levels of IL-1b and TNF-
a among transgenic mice fed with Control, Curcumin or
GSE. It should be noted that these cytokines exist at very
low levels in the serum, which is within the lower range of
sensitivity of the ELISA kits used (8–15 pg/ml) which
might not be sensitive enough to reflect the difference
between groups. Another possible explanation is that the
cytokines in the serum might not have a good correlation to
the cytokines in the brain. The IL-1b, TNF-a and IFN-c
levels in the transgenic mice have not been well charac-
terized. So far limited studies have examined these
cytokines in the APP transgenic mouse model and gener-
ated controversial results, primarily as a result of the low
levels of these cytokines (Mehlhorn et al. 2000; Sly et al.
2001; Abbas et al. 2002; Yamamoto et al. 2007; see review
in Heneka and O’Banion 2007). However, our quantitative
data on the microglia activation by immunostaining dem-
onstrated that the microglia activation was suppressed by
over 70% in animals on the GSE diet. The inflammation
suppression by the GSE diet indicates that the polyphenols
from GSE are also powerful ingredients which inhibit
inflammation in the brain of AD. It is well known that GSE
has a property of anti-inflammation in other inflammation
models such as chemically-induced dermatitis (Li et al.
2001; Bralley et al. 2007), ultraviolet B (UVB) induced
oxidative stress models (Sharma et al. 2007), atheroscle-
rosis model (Vinson et al. 2002) or systemic sclerosis in
patients (Kalin et al. 2002). How the GSE polyphenols in
the present study affect the inflammation is not clear. It is
known that the green tea polyphenol EGCG or GSE sup-
presses NF-kappaB activation and phosphorylation of p38
MAPK and JNK in human astrocytoma U373MG cells
(Kim et al.
2007) or in a UVB-induced oxidative stress
mouse model. As NF-kappaB, p38 MAPK and JNK are the
major signal pathways involving inflammation, it is likely
that the polyphenols from GSE suppress inflammation by
inhibiting these signal pathways. In a human umbilical vein
endothelial cell culture model, GSE significantly inhibited
the expression of adhesion molecule VCAM-1 and acti-
vated peroxisome proliferators-activated receptor gamma
(PPAR gamma) and reduced the content of Von Wille-
brand factor, indicating that GSE may suppress
inflammation by inhibiting the cell inflammatory factor
expression and activating PPAR gamma (Ma et al. 2007).
Other mechanisms such as oxygen free radical scavenging,
anti-lipid peroxidation and inhibition of the formation of
inflammatory cytokines may also be involved (Li et al.
2001). Meanwhile, decrease of Ab accumulation in the
brain may also contribute to the reduced microgliosis
observed in the present study.
In our present study, consumption of GSE or curcumin
did not significantly reduce the GFAP positive astrogliosis,
although Ab pathology and microgliosis in the brain were
significantly attenuated. Significant astrogliosis was also
observed in the brain of wild-type control mice. Our find-
ings are consistent with a recent study showing that area
reactivity of GFAP did not correlate with Ab immunore-
activity in AD patients’ brains, which suggests other
factors such as age-associated events may also contribute
to the astrocyte pathology in the AD brain (Simpson et al.
2008).
Moderate wine consumption has been recommended for
the prevention of AD (Hampl et al. 2002). Considering that
the disease primarily affects the older generation most of
whom are contraindicated to alcohol, polyphenol extracts
from grape seeds might be a better alternative to wine for
the prevention of AD. In a parallel study, we have shown
that the consumption of polyphenols from GSE signifi-
cantly suppressed the genomic instability events associated
with DNA damage in those animals with a high polyphenol
or curcumin diet (Thomas et al. in press), which is in
agreement with other studies from our group showing that
wine polyphenols protect against DNA damage induced by
oxidative stress in vitro and ex vivo (Greenrod and Fenech
2003; Greenrod et al. 2005). In the present study, we have
clearly demonstrated the benefit of GSE as a food additive
in the prevention of AD. Our studies showed that 9 months
of continuous consumption of GSE did not cause any
damage to the liver, as the bilirubin level and amino acid
transferase activities are normal. The food intake and body
weight in the experimental animals are well maintained and
comparable to those of animals fed with the Control diet. In
addition, all animals fed with GSE were found to be normal
with no tumour development or unexpected death. Our
study indicates that GSE is a safe food additive in mice and
therefore it is possible that it may be safely consumed in a
long-term manner in humans to prevent the development of
AD, although this has yet to be tested. As this food additive
has a strong anti-inflammatory effect shown in the previous
studies and our current studies, the consumption of GSE
may be beneficial for chronic inflammatory diseases. Given
12 Neurotox Res (2009) 15:3–14
123
the safety of GSE in long-term use and that no strong
disease-modifying therapeutic and preventive measures are
currently available in clinical settings, consuming GSE
would be promising in developing practical preventive and
therapeutic measures for AD.
Acknowledgements The authors wish to thank Dr Qiao-Xin Li and
Professor Colin Masters from the Department of Pathology, the
University of Melbourne for their advice and input. This work was
supported by grants from the Australian Centre of Excellence for
Functional Foods (MF) and Australian NHMRC (No. 480422, X. F.
Zhou & Y. J. Wang). Y. J. Wang is supported by EIPRS at Flinders
University.
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... Vepsäläinen et al. found that anthocyanin-rich bilberry or blackcurrant extracts can decrease the levels of C-terminal fragment of APP in the cerebral cortex of APP/PS1 mice (APdE9) and reduce behavioral abnormalities associated with AD [140]. It has also been reported that the oral administration of grape-derived polyphenols, composed of catechin and epicatechin in monomeric (~8%), oligomeric (75%), and polymeric forms (~17%), for five months can prevent Aβ oligomerization and attenuate AD-type cognitive impairment in a transgenic mouse model of AD of Tg2576 and APP/PS1 mice [141,142]. A study on the long-term administration of Ginkgo biloba extracts, including flavonols (quercetin, kaempferol, isorhamnetin) and terpenelactone, has also shown that the extracts can considerably decrease the levels of APP in the cortex of Tg2576 mice [143]. ...
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Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity and mortality, for which there is no available cure. Currently, it is generally believed that AD is a disease caused by multiple factors, such as amyloid-beta accumulation, tau protein hyperphosphorylation, oxidative stress, and inflammation. Multitarget prevention and treatment strategies for AD are recommended. Interestingly, naturally occurring dietary flavonoids, a class of polyphenols, have been reported to have multiple biological activities and anti-AD effects in several AD models owing to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties. In this review, we summarize and discuss the existing multiple pathogenic factors of AD. Moreover, we further elaborate on the biological activities of natural flavonoids and their potential mode of action and targets in managing AD by presenting a wide range of experimental evidence. The gathered data indicate that flavonoids can be regarded as prophylactics to slow the advancement of AD or avert its onset. Different flavonoids have different activities and varying levels of activity. Further, this review summarizes the structure–activity relationship of flavonoids based on the existing literature and can provide guidance on the design and selection of flavonoids as anti-AD drugs.
... These kinases appear to promote the effect of flavonoids on the extracellular signal-regulated kinase (ERK) pathway [67]. Flavonoids have a structural similarity to a number of pharmacological ERK signalling pathway modulators [68]. Activation of the cAMP response element-binding protein (CREB) has also been observed as a result of ERK activation, which can result in upregulation of neuroprotective pathways as well as changes in memory and synaptic plasticity [69]. ...
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Alzheimer’s disease (AD) is one of the serious and progressive neurodegenerative disorders in the elderly worldwide. Various genetic, environmental, and lifestyle factors are associated with its pathogenesis that affect neuronal cells to degenerate over the period of time. AD is characterized by cognitive dysfunctions, behavioural disability, and psychological impairments due to the accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles (NFT). Several research reports have shown that flavonoids are the polyphenolic compounds that significantly improve cognitive functions and inhibit or delay the amyloid beta aggregation or NFT formation in AD. Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems including AD. During AD pathogenesis, multiple signalling pathways are involved and to target a single pathway may relieve the symptoms but not provides the permanent cure. Flavonoids communicate with different signalling pathways and adjust their activities, accordingly prompting valuable neuroprotective impacts. Flavonoids likewise hamper the movement of obsessive indications of neurodegenerative disorders by hindering neuronal apoptosis incited by neurotoxic substances. In this short review, we briefly discussed about the classification of flavonoids and their neuroprotective properties that could be used as a potential source for the treatment of AD. In this review, we also highlight the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production.
... Traditionally, grape extracts have been widely utilized for the treatment of a wide range of health problems including inflammation, cardiovascular disease, hypertension, diabetes, cancer, peptic ulcer, microbial infections, etc. (Gupta et al., 2020). Indeed, several studies have demonstrated the anti-inflammatory, antioxidant, and neuroprotective effects of grape extract in vitro and in vivo models of brain injury and neurodegenerative diseases (Pazos-Tomas et al., 2020) including Alzheimer's disease (Wang et al., 2009) and PD, in which the systemic administration of grape seed and skin extract was found to counteract the loss of mesencephalic dopaminergic neurons observed in mice following the unilateral intra-striatal injection of 6-OHDA (Ben Youssef et al., 2021). The process of wine production leads to the generation of a large quantity of grape pomaces, which are generally considered as waste products; however, these pomaces are rich in primary metabolites (i.e., sugars, amino acids, and organic acids) and most importantly in secondary metabolites (i.e., polyphenols) characterized by the presence of relatively varied amounts of phenolic acids (gallic acid), flavanols (catechin, epicatechin, procyanidin B2), and flavonols (quercetin) (Manconi et al., 2020). ...
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Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose ® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT-positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration.
... Mice fed a GSE-rich diet had lower levels of Aβ in their brains and serum. In an experimental model involving a mouse, GSE rich in polyphenols prevents Aβ arrangement and lowers inflammation in the brain, indicating that it is beneficial in preventing AD development [119]. ...
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Alzheimer’s disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder’s reports from Alzheimer’s Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.
... Catechin (CT) is the main component of tea polyphenols. Many studies have shown that CT has a significant effect on antioxidant, anti-cancer [1,2], antibacterial [3,4], and anti-inflammatory abilities [5,6], and CT can reduce lipid production and reduce the incidence rate of cardiovascular and cerebrovascular diseases [7,8], and which can effectively improve the body's immunity, and protect the heavy metals poisoning. It has been widely applicated in food, medicine, and other fields. ...
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In this paper, we explore the adsorption potential of catechin (CT) loaded composite microspheres and provide a new micron scale carrier of functional factor.Chitosan (CS) modified rice porous starch (RPS/CS) was used as a CT adsorption carrier to prepare bioactive CT-loaded composite microspheres ([email protected]/CS). The adsorption kinetics, storage characteristics, and biological activity maintenance of [email protected]/CS were studied in an aqueous solution, and the sustained-release characteristics of [email protected]/CS were studied in vitro during simulated gastrointestinal digestion. An aqueous solution further studied the removal characteristics of adsorbed heavy metal ion Pb²⁺. RPS/CS can significantly improve the ability to adsorb CT. RPS/CS can also significantly improve CT's storage stability, antioxidant stress, and slow-release characteristics, and the sustained release effect in gastric and intestinal juice. [email protected]/CS can be removed Pb²⁺ by adsorbing in the solution, and their adsorption was physical adsorption and chemisorption, but the primary interaction is chemisorption. [email protected]/CS can be used as a micron carrier of new food functional factors, which has potential space for improving and expanding the functional characteristics of its loaded functional factors and the endowing of new functions.
... This in turn, can lower the level of Aβ42 peptide and provide protection against hippocampal cell death (Perry and Greig 2004;Yildirim Simsir et al. 2018). Thus, the DPP-4 inhibitors increase the concentration of GLP-1, leads to decreased production of Aβ42 and its toxicity in AD (Wang et al. 2009;Angelopoulou and Piperi 2018). ICV-STZ had no effect on active GLP-1 levels in the brain which is confirmed by the results of active GLP-1 levels in the cortex and hippocampus in sham control and negative control group. ...
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DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.
... In the AD mouse models, curcumin lowered the levels of Amyloid Beta serum and Amyloid Beta strain in the brain, mainly in the neocortex and hippocampus regions, as well as reduced inflammation and microglia activation [117]. Curcumin can also modulate the processing and phosphorylation of tau protein to prevent the development of NFTs [118][119]. Due to its fluorescent properties and amyloid-beta binding capacity, curcumin has also been proposed as a detection agent for the early diagnosis of plaque deposition in the brain [23]. ...
... In the AD mouse models, curcumin lowered the levels of Amyloid Beta serum and Amyloid Beta strain in the brain, mainly in the neocortex and hippocampus regions, as well as reduced inflammation and microglia activation [117]. Curcumin can also modulate the processing and phosphorylation of tau protein to prevent the development of NFTs [118][119]. Due to its fluorescent properties and amyloid-beta binding capacity, curcumin has also been proposed as a detection agent for the early diagnosis of plaque deposition in the brain [23]. ...
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Alzheimer’s disease (AD) has emerged as a serious and challenging neurological disorder in the ageing population worldwide. The progressive decline of mental health in AD patients causes memory loss, cognition decline, and motor impairment, which impacts adversely on the quality of life of afflicted individuals. Health care costs of mental diseases, dementia and AD are escalating globally, because the AD patients need continuous attention either by the family members or by the health care providers. Also, pharmaceutical treatment and hospital cost of AD is very expensive for the society. Therefore, there is an urgent need to develop cost-effective, affordable, and safe alternative remedies for the prevention/mitigation and management of AD. Plant-derived anti oxidant/anti-inflammation macromolecules (e.g., curcumin, genistein, melatonin, resveratrol, vanillic acid, caffeic acid, berberine) and nutraceuticals (Gingko Biloba) appear to be the safer and cost-effective promising options for the prevention/progression and management of AD patients. The underlying causes and pathological mechanisms of AD are multiple and complex, which include genetic, epigenetic, non-genetic and environmental risk factors. Lifestyle aspects (e.g., excessive tobacco smoking and alcohol abuse), unhealthy dietary habits, accumulation of heavy metals (arsenic, lead, cobalt, mercury) in CNS, and chronic viral infections are considered some other risk factors in memory loss and AD. Brain has relatively low levels of antioxidants and low repair capacity of neuronal cells. Reduced blood supply and impaired mitochondria promote lesser ATP synthesis and energy support in the brain. Many studies have suggested that excessive oxidative stress in the brain leads to the overproduction of free radicals like reactive oxygen species (ROS) and reactive nitrogen species (RNS) from mitochondrial damage and reduction of ATP synthesis. The unabated over production of ROS/RNS cause insults to brain lipids by initiating lipid peroxidation and damage to cellular molecules, resulting in pathological injury and neuronal death. Antioxidant and anti-inflammation phytomolecules, dietary flavonoids, and nutraceuticals have gained significant importance for scavenging the free radicals and producing neuro protective and memory-enhancing effects. Systematic searches were done using PUBMED, EMBASE, Scopus, Google Scholar, ResearchGate, and Web of Science databases. Numerous in vitro and in vivo studies have demonstrated that dietary antioxidant/ anti-inflammation flavonoids, micronutrients (vitamins, trace metals, amino acids), and plant-derived polyphenols synergistically exhibit neuroprotective activity in AD animal models by stimulating transcription of the endogenous antioxidant system in the brain. The aims and objectives of this review are to recapitulate the current knowledge about the pathophysiology of AD and to shed light on the therapeutic strategies being used for slowing down the progression of dementia and cognitive decline. We will also provide an overview of the proposed underlying mechanisms of different nutraceuticals and their recommended dosages in the prevention/mitigation of AD along with a summary of the antioxidant/anti-inflammation ingredients present in patented formulations. Keywords: Alzheimer’s disease, oxidative stress, dementia, cognition decline, nutraceuticals, phytotherapies, polyphenolic nutrients, antioxidant and anti-inflammation diets.
... In addition, GSP prevents tumorigenesis and show chemo-preventive properties against various cancers [23,24]. It may also be effective against the development of Alzheimer's disease and potentially other neurodegenerative disorders [25][26][27]. GSP can also modulate the GI tract; it suppresses DSS-induced colitis in the intestine through the improvement of the intestinal barrier, reduction of oxidative stress, and modulation of inflammatory cytokines and gut microbiota, suggesting its potential applicability as an adjuvant therapy for ulcerative colitis [4,28]. GSP has protective roles against inflammatory bowel disease through its ability to influence gut inflammation, the expression of tight junction proteins, and gut microbiota [7]. ...
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Grape seed is an important natural bioactive product with various health benefits. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal (GI) tract. The present study investigated the effects of grape seed powder (GSP) on ICC properties and GI motility. GSP depolarized the pacemaker potentials of ICCs in a dose‑dependent manner. Y25130 or SB269970 slightly inhibited GSP‑induced effects. However, Y25130 and SB269970 together completely blocked GSP-induced effects. In the presence of inhibitors of protein kinase C, protein kinase A, or mitogen-activated protein kinase, GSP‑induced ICC depolarization was inhibited. GSP increased the intestinal transit rate in normal mice and in mice with acetic acid-induced GI motility disorder. In addition, the levels of motilin and substance P were elevated after GSP dosing. These results demonstrate that GSP can regulate GI motility, and therefore, it is a potential therapeutic agent for treating GI motility disorders.
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Overexposure to mental stress throughout life is a significant risk factor for the development of neuropsychiatric disorders, including depression and anxiety. The immune system can initiate a physiological response, releasing stress hormones and pro–inflammatory cytokines, in response to stressors. These effects can overcome allostatic physiological mechanisms and generate a pro–inflammatory environment with deleterious effects if occurring chronically. Previous studies in our lab have identified key anti–inflammatory properties of a bioavailable polyphenolic preparation BDPP and its ability to mitigate stress responses via the attenuation of NLRP3 inflammasome-dependent responses. Inflammasome activation is part of the first line of defense against stimuli of different natures, provides a rapid response, and, therefore, is of capital importance within the innate immunity response. malvidin–3–O–glucoside (MG), a natural anthocyanin present in high proportions in grapes, has been reported to exhibit anti-inflammatory effects, but its mechanisms remain poorly understood. This study aims to elucidate the therapeutic potential of MG on inflammasome-induced inflammation in vitro and in a mouse model of chronic unpredictable stress (CUS). Here, it is shown that MG is an anti-pyroptotic phenolic metabolite that targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase–1 and IL–1β protein levels in murine primary cortical microglia and the brain, as its beneficial effect to counteract anxiety and depression is also demonstrated. The present study supports the role of MG to mitigate bacterial-mediated inflammation (lipopolysaccharide or LPS) in vitro and CUS-induced behavior impairment in vivo to address stress-induced inflammasome-mediated innate response.
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Background: Our goal was to forecast the global burden of Alzheimer’s disease and evaluate the potential impact of interventions that delay disease onset or progression. Methods: A stochastic, multistate model was used in conjunction with United Nations worldwide population forecasts and data from epidemiological studies of the risks of Alzheimer’s disease. Results: In 2006, the worldwide prevalence of Alzheimer’s disease was 26.6 million. By 2050, the prevalence will quadruple, by which time 1 in 85 persons worldwide will be living with the disease. We estimate about 43% of prevalent cases need a high level of care, equivalent to that of a nursing home. If interventions could delay both disease onset and progression by a modest 1 year, there would be nearly 9.2 million fewer cases of the disease in 2050, with nearly the entire decline attributable to decreases in persons needing a high level of care. Conclusions: We face a looming global epidemic of Alzheimer’s disease as the world’s population ages. Modest advances in therapeutic and preventive strategies that lead to even small delays in the onset and progression of Alzheimer’s disease can significantly reduce the global burden of this disease.
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Recent studies suggest that moderate red wine consumption reduces the incidence of Alzhei- mer's disease (AD) clinical dementia. Using Tg2576 mice, which model AD-type amyloid beta-protein (A) neuropathology, we tested whether moderate consump- tion of the red wine Cabernet Sauvignon modulates AD-type neuropathology and cognitive deterioration. The wine used in the study was generated using Caber- net Sauvignon grapes from Fresno, California, and was delivered to Tg2576 in a final concentration of 6% ethanol. We found that Cabernet Sauvignon signifi- cantly attenuated AD-type deterioration of spatial mem- ory function and A neuropathology in Tg2576 mice relative to control Tg2576 mice that were treated with either a comparable amount of ethanol or water alone. Chemical analysis showed the Cabernet Sauvignon used in this study contains a very low content of resveratrol (0.2 mg/L), 10-fold lower than the minimal effective concentration shown to promote A clearance in vitro. Our studies suggest Cabernet Sauvignon exerts a ben- eficial effect by promoting nonamyloidogenic process- ing of amyloid precursor protein, which ultimately prevents the generation of A peptides. This study supports epidemiological evidence indicating that moder- ate wine consumption, within the range recommended by the FDA dietary guidelines of one drink per day for women and two for men, may help reduce the relative risk for AD clinical dementia.—Wang, J., Ho, L., Zhao, Z., Seror, I., Humala, N., Dickstein, D. L., Meenakshi- sundaram, T., Percival, S. S., Talcott, S. T., Pasinetti, G. M. Moderate consumption of Cabernet Sauvignon attenuates A neuropathology in a mouse model of Alzheimer's disease. FASEB J. 20, 2313-2320 (2006)
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01-02-02 The goal was to forecast the global burden of Alzheimer’s disease and evaluate the potential impact of interventions that delay disease onset or progression.
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Interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-6 (IL-6) were measured in the cerebrospinal fluid (CSF) and plasma of 12 control subjects, 11 sporadic Alzheimer's disease (AD) and 22 de novo Parkinson's disease (PD) patients using high sensitivity enzyme-linked immunosorbent assays (ELISA). IL-1β and IL-6 contents were significantly elevated in the CSF of de novo PD and AD patients in comparison to the control group. In contrast, the plasma levels were not significantly affected. IL-2 contents in the CSF and plasma samples were unchanged in the three groups compared. Because the two cytokines IL-1β and IL-6 are known to play a key role in the interaction between the nervous and immune system, e.g. in the so-called acute phase response, our results support the involvement of immunological events in the complex process of neurodegeneration in AD and PD.
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In the United States, the leading determinants of morbidity and mortality are rooted in behavioral choices related to eating habits, exercise, tobacco, alcohol consumption, and stress reduction. Scientific data consistently provide evidence that diet plays an important role in health promotion and disease prevention. Healthy eating habits—coupled with other healthful lifestyle behaviors—have the potential to reduce the risk of chronic disease. Health care typically assumes a curative or treatment role in the United States. However, dietetics professionals arc shaping an alternate view of health, which includes developing healthy public policies, creating safe and supportive environments, building communities and coalitions, and reorienting health services to include health promotion as a primary approach to delivering health care. Individual-level approaches, such as counseling and group education, have been employed most often in modifying health behaviors. However, population-level approaches that affect availability of or access to healthy foods, opportunities for physical activity, and other healthy lifestyle determinants also are important. Dietetics professionals have pivotal roles in both individual- and population-level approaches.