Impact of apoE genotype on oxidative stress, inflammation and disease risk

Article (PDF Available)inMolecular Nutrition & Food Research 52(1):131-45 · January 2008with137 Reads
DOI: 10.1002/mnfr.200700322 · Source: PubMed
Abstract
Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary advantage, as it has been shown to offer protection against certain infectious disease, in Westernised societies it is associated with increased morbidity and mortality, and represents a significant risk factor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an important modulator of many stages of lipoprotein metabolism and traditionally the increased risk was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflammatory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated with the epsilon4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflammatory properties of apoE is the focus of the current review. Furthermore, current information on the impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associations are discussed with a view to identifying particular lifestyle strategies that could be adapted to counteract the 'at-risk' E4 genotype.
131
Mol. Nutr. Food Res. 2008, 52, 131 145 DOI 10.1002/mnfr.200700322
Review
Impact of apoE genotype on oxidative stress,
inflammation and disease risk
Laia Jofre-Monseny
1
, Anne-Marie Minihane
2
and Gerald Rimbach
1
1
Institute of Human Nutrition and Food Science, Christian Albrechts University of Kiel, Kiel, Germany
2
School of Chemistry, Food Biosciences and Pharmacy, University of Reading, Reading, UK
Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary
advantage, as it has been shown to offer protection against certain infectious disease, in Westernised
societies it is associated with increased morbidity and mortality, and represents a significant risk fac-
tor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an
important modulator of many stages of lipoprotein metabolism and traditionally the increased risk
was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the
multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk
may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflamma-
tory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents
and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated
with the e4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflamma-
tory properties of apoE is the focus of the current review. Furthermore, current information on the
impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associa-
tions are discussed with a view to identifying particular lifestyle strategies that could be adapted to
counteract the
,
at-risk’ E4 genotype.
Keywords: Alzheimer disease / Apolipoprotein E / Cardiovascular disease / Inflammation / Oxidative stress /
Received: August 15, 2007; revised: October 18, 2007; accepted: October 19, 2007
1 Introduction
Cardiovascular disease (CVD) is the leading cause of mor-
tality worldwide, with latest statistics suggesting that it is
responsible for 17.5 million deaths annually [1] with sev-
eral fold higher numbers thought to suffer from CVD-
related morbidity. Furthermore, it is estimated that there are
currently about 18 million people worldwide with Alz-
heimer's disease (AD) [2], with aging populations demo-
graphics associated with an ever-increasing incidence.
Since the characterisation of the almost complete human
genome was first published in 2001 and the subsequent
description of gene variations, which are available in public
databases, there has been a large research focus on the asso-
ciation between common single nucleotide polymorphisms
(SNPs) in critical genes and risk of diseases. This has not
only led to a better understanding of the patho-physiologi-
cal mechanisms of such diseases, but also to the identifica-
tion of genotypic biomarkers that could potentially be used
as predictors of future disease risk.
One of the most studied gene has been the apolipoprotein
E (apoE) gene, with 3891 PubMed papers and 54 individual
SNPs (www.ncbi.nlm.nih.gov) published at the time of
writing this review. The most widely described SNPs,
which are the focus of the current review, are undoubtedly
those that give rise to the apoE2, E3 and E4 protein iso-
forms. The E4 allele, which is present in approximately
25% of the Caucasian population, has been associated with
increased risk of CVD, and it is the major known genetic
risk factor for maturity onset AD. In addition, apoE4 has
been shown to modulate the risk of many other disorders
(see below).
The mechanisms by which apoE genotype has an impact
on these diseases is not fully understood. Traditionally, the
4050% higher risk of CVD associated with the apoE4
allele [3] was attributed to small increments in circulating
cholesterol and triglycerides (TAG) levels observed in
Correspondence: Professor Gerald Rimbach, Institute of Human Nu-
trition and Food Science, Christian Albrechts University of Kiel, Her-
mann-Rodewald-Strasse 6, 24098 Kiel, Germany
E-mail: rimbach@foodsci.uni-kiel.de
Abbreviations: Ab, amyloid-b; AD, Alzheimer's disease; apoE, apoli-
poprotein E; CHD, coronary heart disease; CVD, cardiovascular dis-
ease; GSH, glutathione; SNP, single nucleotide polymorphisms;
TBARS, thiobarbituric acid reactive substances
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
apoE4 carriers. However, it is recognised that the relatively
moderate effects on the lipid profile (see review [4]) cannot
be the sole explanation for the genotype-mediated disease
differential and, in addition, it does not explain the associa-
tions with AD and other conditions. Recently, two novel
key mechanisms by which apoE could affect many biologi-
cal processes have been recognised. These are its antioxi-
dant and inflammation modulatory properties, which have
been shown to be altered by genotype, and could therefore
help explain many of the apoE isoform-disease associations
(Fig. 1). The aim of this review is to summarise the existing
evidence of these two aspects of apoE function in the con-
text of the associations of apoE4 and disease risk.
2 ApoE and the impact of genotype on apoE
structure and function
The first identified role of apoE was as a regulator of lipo-
protein metabolism: it is involved in hepatic lipoprotein
secretion, lipoprotein metabolism in the circulation, and
serves as a high-affinity ligand for cellular lipoprotein
uptake. However, apoE has been shown to exert multiple
functions, independent of its role in lipid metabolism.
ApoE is mainly synthesised by the liver but is also produced
in tissues such as the brain and macrophages. It is thought
that around 2040% of apoE stems from extra-hepatic tis-
sues [57]. In the brain, apoE has been shown to protect
Tau from phosphor ylation [8], to influence the metabolism
of amyloid-b (Ab) [9] and participate in neuronal repair
[10]. Macrophage-derived apoE is abundant in the lesion
site of atherosclerotic plaques, where it has been shown to
influence many processes such as platelet aggregation [11],
macrophage cholesterol efflux [12, 13], the expression of
adhesion molecules by the endothelial cells [14] and inhibi-
tion of smooth muscle cell proliferation and mig ration [15].
ApoE is an arginine-rich protein containing 299 amino
acid residues (34 kDa) and results from the cleavage of a
317 amino acid primary translation product [16]. Its gene
has been mapped to chromosome 19 in a cluster with
APOC1 and APOC2. Three common alleles e2 (rs 7412),
e3, and e4 (rs 429358), result in apoE2, apoE3 and apoE4
isoforms, respectively. ApoE isoforms differ in amino acid
residues at positions 112 and 158 [17]. ApoE3 is the most
common isoform and contains cysteine and arginine at
these sites, whereas apoE2 has two cysteines and apoE4
two arginines (Table 1). The amino acid exchanges lead to
structural differences that have an impact on the protein
functionality. On the one hand, the substitution of an argi-
nine by a cysteine at position 158 in apoE2, results in a 50
100-fold weaker binding affinity of the protein for cell sur-
face LDL receptors [18, 19]. As a result, homozygosity for
apoE2 is associated with type III hyperlipoproteinaemia, a
condition characterised by high circulating TAG levels.
On the other hand, substitution of cysteine by arginine at
position 112 in apoE4, does not affect the binding affinity
to the LDL receptors, but changes the conformation of the
side chain of Arg61. This is thought to impact on the chem-
ical and thermal stability of the protein and in the for mation
of folding intermediates, with apoE2 showing the greatest
stability and least formation of intermediates, while apoE4
shows the opposite properties, forming a typical molten
globule configuration [20]. In addition to stability, it is
thought that these differences in apoE4 protein folding
explain the differential lipoprotein binding preferences [20,
21], with apoE4 binding preferably to larger liquid-rich
lipoproteins (VLDL and LDL) and apoE2 and apoE3 pre-
ferring smaller lipoproteins such as HDL. This in turn is
thought to be largely responsible for the moderate incre-
ments (l8%) in LDLC observed in apoE4 carriers [4].
Additionally, this impact of apoE genotype on protein
structure is being increasingly shown to modify the effects
of apoE on the above-mentioned processes unrelated to
lipid metabolism. Of importance, apoE has been demon-
strated to possess antioxidant properties in a genotype-
dependent manner (apoE2 A E3 A E4), and has been also
shown to influence the inflammatory response, two com-
mon pathological hallmarks of CVD and AD (Fig. 1).
3 ApoE genotype and disease risk
Extensive epidemiological data are available which demon-
strates an association between apoE genotype and risk of
CVD and AD. The meta-analysis of Song et al. [3], a review
of 48 studies, demonstrated that compared to the wild-type
E3/E3 genotype, carriers of the e4 allele had a 42% higher
risk of coronar y heart disease (CHD). However, the associa-
tion between apoE polymorphism and stroke is still contro-
versial [22, 23]. Case-control studies of apoE genotype and
longevity reveal that, in elderly populations, there is a defi-
cit in apoE4 in comparison to younger populations [24],
which is mainly attributed to the higher CVD incidence.
132
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Figure 1. The multifunctional role of ApoE; MU Macrophage,
Ab Amyloid beta
Mol. Nutr. Food Res. 2008, 52, 131 145
Furthermore, the e4 allele is a firmly established genetic
risk factor for AD. In a meta-analysis conducted by Bertram
et al. [25], odds ratios of 4.3 and 15.6 were noted for E3/E4
and E4/E4 individuals relative to E3/E3, individuals.
Although not so widely studied, apoE genotype has also
been associated with several other diseases/disorders
(Table 2). For instance, apoE4 is associated with poorer out-
come following traumatic brain injury [26, 27] and with
increased post-operative cognitive dysfunction [28, 29].
Although apoE genotype is not associated with an increased
risk of developing multiple sclerosis, apoE4 is found to be a
predisposing factor to a faster disease progression [30].
Additionally, it has also been related to increased risk of
HIV-associated dementia [31]. Altogether, this highlights
that apoE plays an essential role in neurobiology. ApoE4
has also been observed to be associated with psoriasis, a
chronic inflammatory skin disease [32] and has been sug-
gested to be a genetic risk factor for left ventricular failure
in b-thalassemia. This disease is characterised by haemo-
lytic anaemia, with consequent iron overload and chronic
tissue damage [33]. Therefore, in general, an apoE4 geno-
type has been associated with increased risk of diseases
characterised by oxidative stress and a pro-inflammatory
status. However, the strength of the association varies
widely between different populations, indicating an impact
of other genetic variants and environmental variables on
apoE-disease association.
In contrast, apoE4 has been shown to confer protection
against age-related macular degeneration [34]. Although
the mechanism remains unknown, it is hypothesised that
apoE genotype-mediated differences in membrane dynam-
ics due to differences in apoE conformations could lead to
altered transport of lipids and cholesterol in apoE4 carriers,
avoiding the formation of drusen, characteristic structures
formed in age-related macular degeneration [35]. In addi-
tion, apoE4 has been shown to have a role in protecting
against some infectious diseases [36]. For instance, apoE4
is associated with less severe Giardia infections in Brazilian
shantytown children [37] and with protection of children
against the outcomes of early childhood diarrhoea [36].
ApoE4 has also been shown to be protective against liver
damage caused by the hepatitis C virus [38]. Therefore,
apoE4 may have provided initial evolutionary advantages in
pathogen resistance, particularly in situations of malnour-
ishments. The higher incidence of the e4 allele in pre-indus-
trialised countries is consistent with this theory [4]. For
these reasons, the e4 allele is considered a “thrifty” geno-
type, providing advantages in ancestral or pre-industrialised
populations. However, in Westernised populations, where
chronic non-infectious disorders are the major killers, the
apoE4 genotype is likely to be non-advantageous.
4 ApoE genotype and oxidative stress
The antioxidant properties of apoE were first identified in
the middle of the last decade [3942]. Soon afterwards
Miyata and Smith [43] postulated that the apoE genotype
could influence the antioxidative properties of the protein
and thereby impact on both CVD and AD (Table 3, which
details studies examining the association between apoE
genotype and oxidative status). They showed an antioxidant
activity in the order apoE2 A E3 A E4, tested using various
techniques including the chemiluminescence antioxidant
assay, a copper-mediated lipoprotein oxidation assay meas-
ured by thiobarbituric acid reactive substances (TBARS)
and a copper-mediated lipoprotein assay measured by diene
formation. Since then, there have been several additional
studies that have demonstrated that apoE4 is associated
with increased oxidative stress (see below).
Due to the strong association of apoE4 with AD, most
work has been done in relation to the pathophysiology of
this condition. On the one hand, studies with AD patients
have revealed that apoE4 is associated with increased lipid
peroxidation in post-mortem brains [4446] and with ele-
vated hydroxyl radical levels in blood [47]. However, no
impact of genotype on blood antioxidant enzymes were evi-
dent [47, 48]. In mice, it has been shown that Ab induction
of oxidation in isolated synaptosomes leads to increased
reactive oxygen species formation in mice expressing
apoE4 relative to apoE3 [49]. Furthermore, Yao et al. [50]
found increased levels of F
2
-isoprostanes in brains of apoE4
male mice, but found no genotype differences in female
mice.
133
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 1. Structure and action pf apoE isoforms
Isoform SNP ID Residues LDL receptor
binding affinity
Lipoprotein
affinity
Associated lipid changes
112 158
apoE2 rs7412 Cys Cys a2% HDL Type III hyperlipoproteinae-
mia (increased triglyceride
levels)
apoE3 Cys Arg High HDL
apoE4 rs429358 Arg Cys High VLDL, CM Moderate l8% increased
LDL-cholesterol
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
More recently a new body of evidence has emerged, from
both human observational and cell culture studies, indicat-
ing a role of apoE genotype on oxidative status measures,
relevant to the progression of CVD. In a study aimed at
assessing the impact of genotype on risk of CHD, Humph-
ries and co-workers [51] elucidated a highly significant
genotypesmoking interaction, with apoE4 carriers being
more susceptible to smoking damage (a major source of
oxidative stress) than the non-apoE4 individuals. In
,
never’
smokers, there was no genotype effect on risk of CVD.
However, in smokers, the risk was 1.68 (95% CI 1.01
2.83) and 3.17 (1.82 5.5) in men homozygous for e3 and
for e4 carriers, respectively. This apoE genotypesmoking-
CHD risk interaction appears to be robust as it has since
been confirmed in several additional studies [5354]. It
has been hypothesised that the lower antioxidant capacity
of apoE4 relative to other isoforms is responsible for the
exacerbation of the detrimental effects of tobacco smoking.
Furthermore, a number of studies have examined an
impact of apoE genotype on oxidative status-dependent
mediators or biomarkers of oxidative stress. It was shown
that in smokers, but not in non-smokers, apoE4 subjects
exhibited l30% increased oxidised LDL (ox-LDL), while
apoE2 had l30% higher total antioxidant status, measured
as the capacity to inhibit the peroxidase-mediated forma-
tion of the 2,2-azino-bis-3-ethylbensthiazoline-6-sulfonic
acid (ABTS
+
) radical [53]. Consistent with these findings,
in a mixed group of smokers and non-smokers with total
cholesterol A200 mg/100 mL, apoE4 carriers showed an
l30% increase in F
2
-isoprostanes [55]. Furthermore, in a
study with post-menopausal women, serum concentration
of malondialdehyde-modified LDL (MDA-LDL) in the fol-
lowing order E4 A E3 A E2 [56] were observed. In contrast,
in transgenic mice expressing either apoE3 or apoE4, we
found no differences in the antioxidant defence system in
different tissues and only a tendency towards increased F
2
-
isoprostanes was observed in apoE4 mice (Jofre-Monseny,
unpublished data). Although these results may seem contra-
dictory, they are in accordance with the hypothesis of Tal-
mud et al. [53], who suggested that an additional source of
oxidative stress is needed to observe an apoE genotype-
mediated impact on oxidative status. To date, human obser-
vational studies have largely focused on smoking status as a
source of oxidative stress. Although there is no evidence
currently available, it is likely that apoE genotype differen-
ces will also be apparent in other subgroups with a risk of a
compromised oxidative status, such as trained athletes or
individuals with a low fruit and vegetable intake.
With the purpose of gaining a deeper understanding of
the possible role of apoE antioxidant properties in the proc-
ess of atherogenesis, we have recently investigated the
impact of apoE genotype on macrophage oxidative status.
Macrophages are not only of interest because they are key
cells in the development of atherosclerosis, but also because
they are the cells that produce and secrete apoE in the vas-
cular wall. Although apoE has been shown to have multiple
functions within the macrophage itself and adjacent cells
found in the vascular wall [11, 12], the contribution of the
antioxidant capacity of apoE or the impact of genotype on
antioxidant function on these processes is relatively
unknown. We found that apoE genotype had no influence
on protection against hydrogen peroxide-induced cytotox-
icity or in the intracellular levels of GSH. However, cells
secreting apoE4 showed higher membrane oxidation and
produced more nitric oxide (NO) and superoxide anion rad-
icals (O
2
9
) upon stimulation with LPS and with phorbol
myristate acetate (PMA) [57], respectively.
In addition, there are a limited number of in vitro studies
that have focused on the impact of apoE genotype on LDL
oxidation. It has been shown, in a copper-mediated and in a
enhanced chemiluminescence reaction dependent on horse-
radish peroxidase model that apoE inhibits lipoprotein oxi-
dation in an isoform-dependent manner (E2 A E3 A E4) [43,
58, 59]. In contrast, in a model, independent of metal induc-
tion, no impact of isoform was evident with all forms of
apoE inhibiting LDL oxidation [58]. Fur thermore, Pham
and co-workers [59] identified the receptor-binding domain
(residues 141155) as responsible for the LDL oxidation
inhibitory properties of apoE.
The molecular mechanisms responsible for the antioxi-
dant capacity of apoE have not as yet been fully elucidated.
The in vitro models of copper-catalysed LDL oxidation aim
to mimic the in vivo oxidation process, and measure a com-
bination of radical scavenging and transition metal chela-
tion. Miyata and Smith [43] hypothesised that apoE exerted
its antioxidant properties by metal sequestration, and de-
monstrated that apoE was retained by metal columns, with
maximal retention by the cupric column; however, differen-
134
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 2. ApoE4 associations to disease risk
ApoE4 increased risk ApoE4 decreased risk
Alzheimer's disease [101, 102]
Traumatic brain injury outcome [26, 27]
Postoperative cognitive dysfunction [28, 29]
HIV-associated dementia [31]
Cardiovascular disease [103]
Left ventricular failure in b-thalassemia [33]
Psoriasis [32]
Hepatitis C [38]
Diarrhoea in children [36, 37]
Age-related macular degeneration [34, 35]
Mol. Nutr. Food Res. 2008, 52, 131 145
135
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 3. Summary of the studies on apoE and oxidative stress
Author, year Model Species Parameter/biomarker Outcome
Miyata and Smith 1996
[43]
Neuronal cells and
in vitro assays
CC B12 neurones protection from hydro-
gen peroxide
Antioxidant mediated quenching of
an enhanced chemiluminescence
Inhibition of copper mediated lipopro-
tein oxidation
Copper mediated lipoprotein oxidation
(T
1/2
)
Metal binding (cupric, ferrous, ferric
and zinc)
–E2A E3 A E4 (condi-
tioned media)
–E2A E3 A E4
–E2A E3 A E4
–E2A E3 A E4
E2=E3=E4
Fernandes et al. 1999
[48]
AD patients and
controls
H MDA in plasma and erythrocytes,
enzymatic and non-enzymatic defence
in plasma, erythrocytes, platelets and
leukocytes
Uric acid and catechol-O-methyl-
transferase
E2 = E3 = E4
–E4a E3 = E2
Ramassamy et al. 1999
[44]
AD patients
Frontal cortex
H Lipid oxidation (TBARS)
Catalase, Glutathione peroxidase
SOD
–E4A E3
–E4a E3
–E3=E4
Ramassamy et al. 2000
[45]
AD patients
Hippocampus
H TBARS in hippocampus
Catalase, GPx, GSH
–E4A non-E4
–E4a E3
Ihara Y et al. 2000 [47] AD patients H Hydroxyl radical levels
Superoxide dismutase activity and
protein levels
–E4A non-E4
–E3=E4
Jolivalt et al. 2000 [104] In vitro assay Susceptibility to oxidation of the
protein
–E4A E3 A E2
Pedersen et al. 2000 [60] In vitro assay Interaction of pure apoE with
4-hydroxynonenal
–E2A E3 A E4
Tamoka et al. 2000 [46] Post-mortem
brain AD
H TBARS generated de novo after
oxidative stimuli
E4/E4 A E3/E4 A E3/E3
A E3/E2
Humpries et al. 2001 [51] Prospective cardio-
vascular surveillance
(Second Northwich
Park Heart Study)
(male)
H Gene-environment interactions Smoking increases risk
of coronary artery dis-
ease particularly in E4
End points: fatal coro-
nary heart disease,
non-fatal myocardial in-
farction, coronary ar-
tery surgery and silent
myocardial infarction
Lauderback et al. 2002
[49]
Mice apoE3
and apoE4 brain
M Reactive oxygen species formation
and protein and lipid oxidation
in isolated synaptosomes
–E4A E3 = E2
Mabile et al. 2003 [58] Metal induced and
macrophage LDL
oxidation
CC Oxidation of LDL by AAPH (free
radical scavenging activity)
LDL oxidation by copper (TBARS and
LDL electrophoretic mobility)
Cell mediated oxidation model- mea-
surement in LDL containing medium of
LA and AA consumption, TBARS,
LDL electrophoretic pattern
E2 = E3 = E4
–E2A E3 A E4
–E3=E4A E2 ( Results
due to increased cho-
lesterol efflux in E2;
more substrate in me-
dium susceptible to oxi-
dation of LDL)
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
ces between isoforms were not apparent in this assay. Alter-
natively, Pham et al. [59] argued that the peptide that is
responsible for the inhibition of LDL oxidation is a region
rich in positively charged amino acids, so that a direct inter-
action with the positively charged copper ion is unlikely,
and support, therefore, a free radical scavenging activity of
this region. Pedersen et al. [60] suggest that apoE may have
a role in binding to 4-hydroxynonenal (HNE), and thereby
have a detoxifying role. In these in vitro studies, it was
shown that E2 A E3 A E4 are able to bind HNE.
Altogether, it appears evident that apoE genotype influ-
ences the antioxidative capacity of the lipoprotein. How-
ever, further studies are needed to gain insight into the
molecular basis of the association, and also to establish the
relative importance of apoE genotype-mediated differences
in oxidative status to the pathogenesis of CVD and AD.
5 ApoE genotype and inflammation
The immunosuppressive properties of apoE were first
described almost two decades ago, with the earliest indica-
tions originating from investigations on T cell proliferation
[6163] (Table 4, which details studies examining the asso-
ciation between apoE and immune function and inflamma-
tion). Later, it was shown that apoE deficiency impaired the
immune response to Listeria monocytogenes, Klebsiella
pneumoniae and LPS [6466]. Almost in parallel to inves-
tigations of the differential antioxidant effects of apoE iso-
forms, the differential inflammation modulatory proper ties
of the protein isoforms were examined [67 74]. These
studies were also conducted mainly using models of AD
and brain inflammation.
5.1 Inflammation in relation to AD
In 1998, Egensperger and co-workers [68] demonstrated
that the microglial activation in frontal and temporal corti-
ces in AD brains increased in an apoE4-allele-dose manner.
However, most of our current evidence stems from trials
with rodents, either engineered to express human apoE3 or
apoE4, or used to create primary cell culture in which
recombinant apoE3 or apoE4 protein is added. In mixed
neuronal-glial cultures, addition of both recombinant
136
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 3. Continued
Author, year Model Species Parameter/biomarker Outcome
Yao et al. 2004 [50] Mice apoE3
and apoE4 brain
M–F
2
-Isoprostances in brain Male: E4 A E3
Female:E4 = E3
Tsuda et al. 2004 [105] Postmenopausal
women
H Serum concentration of malondialde-
hyde-modified low-density lipoprotein
(MDA-LDL)
–E4A E3 A E2
Talmud et al. 2005 [53] Framingham Offspring
Study (men)
H CVD risk In non smokers: E2 =
E3 = E4
In smokers: E4 A E2 A
E3 Genotype
smoking interaction
Caucasian patients with
diabetes (males and fe-
males)
H Ox-LDL
Total antioxidant status
In non smokers: E2 =
E3 = E4
In smokers: E2 = E3 a
E4
In non smokers: E2 =
E3 = E4
In smokers: E2 = E3 A
E4
Dietrich et al. 2005 [55] 274 subjects (males
and females)
H–F
2
-isoprostanes E4 A non E4 (in subjects
with total cholesterol A
200 mg/100 mL)
Pham et al. 2005 [59] In vitro Inhibition of copper mediated lipopro-
tein oxidation (conjugated diene forma-
tion)
–E3A E4
Jofre-Monseny
et al. 2007 [57]
Macrophages CC (M) Membrane oxidation
Nitric oxide and superoxide anion radi-
cal production
glutathione, a-tocopherol
–E4A E3
–E4A E3
–E3=E4
H, human; M, mouse; R, rat; CC, cell culture.
Mol. Nutr. Food Res. 2008, 52, 131 145
137
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 4. Summary of the studies on apoE immune function and inflammation
Author, year Model Species Parameter Outcome
Pepe and Curtiss 1986
[61]
ApoE isolated from
plasma
H Mitogen induced lymphocyte
proliferation ([
3
H]thymidine uptake)
ApoE immunosuppres-
sive
Kelly et al. 1994 [62] T lymphocytes
Mitogen: PHA, PMA
+ PHA, OKT3
H Mitogen induced lymphocyte
proliferation ([
3
H]thymidine uptake)
IL2
ApoE suppresses
T-cell proliferation by
decrease of IL2 (activ-
ity levels, but not
mRNA or protein)
Mistry et al. 1995 [63] ApoE isolated from
patients
Peripheral blood mono-
nuclear cells. Mouse
spleen cells
H/M Cell cycle ApoE blocks growth
factor-responsive T-
cells in the G1
A
phase
of the cell cycle.
Laskowitz et al. 1997 [67] Mixed neuronalglial
cultures from apoE
deficient mouse. Addi-
tion of recombinant
apoE3 or E4. LPS ad-
ministration
M TNF-a ApoE reduce TNFa se-
cretion following LPS
stimulation (E3 = E4)
need of preincubation
to observe the effects
exogenous source
of apoE may be insen-
sitive to isoform differ-
ences??
Roselaar and Daugherty
1998 [64]
ApoE deficient mice M Immune response to L. monocyto-
genes
Macrophage activation
TNFa
ApoE deficiency
causes impaired im-
mune response
ApoE deficiency
causes enhanced mac-
rophage
ApoE deficiency
causes inflammation
Sthr et al. 1998 [106] Monocytes in
peripheral blood
H Differentiation of mononuclear phago-
cytes. CD16a (indicates Fc-receptor-
dependent phagocytic activity)
(E4/E4 A E3/E3)
Egensperger et al. 1998
[68]
AD brains H Microglial activation in frontal and
temporal cortices
E4/E4 A E4/E3 A E3/E3
de Bont et al. 1999 [65] ApoE deficient mice
Intravenous LPS
administration
M Immune response to LPS and
K. pneumoniae
TNFa, IL1a, IL1b, IL6
ApoE protects against
LPS and K.pneumo-
niae
ApoE decreased TNFa
but IL1a, IL1b and IL6
did not differ
Lynch et al. 2001 [69] Mixed glial culture of
apoE deficient mice.
LPS exposure
Mice vs apoE deficient
mice. Intravenous ad-
ministration of LPS
M mRNA TNF-a and IL6 ApoE deficient A wild
type
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
138
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 4. Continued
Author, year Model Species Parameter Outcome
Van Oosten et al. 2001
[66]
Rats and mice
Intravenous LPS ad-
ministration
R M apoE serum levels
Cytokine production
i.v. LPS administration
increases apoE serum
levels
ApoE prevents LPS-in-
duced production of cy-
tokines and subse-
quent death physio-
logical role of apoE in
protecting against sep-
sis
Drabe et al. 2001 [82] Patients undergoing
cardiopulmonary by-
pass
H IL8 and TNF-a release by monocytes E4 A E3 Increased
systemic inflammatory
response in ApoE4 car-
riers
Tenger and Zhou 2003
[107]
T cells and macro-
phages isolated from
apoE deficient mice and
wild type
Stimulation with INF
c
M Expression of CD40 and CD80
Major histocompatibility complex class
II molecules I-A.
ApoE deficiency
causes higher expres-
sion of CD40 and CD80
and also o f the major
histocompatibility com-
plex class II molecules
I-A
Lynch et al. 2003 [70] Targeted replacement
mice apoE3 and apoE4.
Intravenous LPS ad-
ministration
M Systemic and brain TNF-a and IL6 E4 A E3
apoE (133-149) (recep-
tor binding region)
suppression of inflam-
mation
Guo et al. 2004 [71] Mixed glia (95% astro-
cytes, 5% microglia)
from rats
Stimulated with LPS
and Ab. Exogenous
apoE administration
M–Ab induced NO synthase, COX-2 When stimulated with
LPS and Ab: anti-in-
flammatory role of
apoE
But exogenous apoE
alone induces IL1b
(E4 A E3) overpro-
duction of apoE may
exacerbate inflamma-
tion
Mrz et al. 2004 [85] 739 subjects with
stable angiographic
coronary artery disease
(CAD), 570 control
H CRP
Fibrinogen and white cell count
–E4a E3 aE2
E2 = E3 = E4
Ophir 2005 [72] Mice E3 E4 brain
LPS injection
M Expression of inflammation related
genes (mRNA and protein levels)
–NFjB activation
E4 higher and more
prolonged than in E3
(Changed genes en-
riched in NFkB ; E4 A
E3)
–E4A E3
Maezawa et al. 2006 [73] Targeted replacement
mice E2, E3, E4
Microglia (LPS activa-
tion)
M Microglia activation induced neurone
cytotoxicity
Microglia p38-MAPK-dependent cyto-
kine activation
–E4A E3 A E2
–E4A E3 A E2
Maezawa et al. 2006 [74] Targeted replacement
mice E2, E3, E4
Astroglia (LPS activa-
tion)
M Primary astrocyte cytokine secretion
–NFjB
–E2A E3 A E4
–E2A E3 A E4
Mol. Nutr. Food Res. 2008, 52, 131 145
apoE3 and apoE4 reduced LPS-induced TNFa secretion,
with no differences between isoforms observed [67]. In
contrast, a later study with transgenic mice showed that sys-
temic and brain TNFa and IL6 secretion were higher in
apoE4 than in apoE3 mice [70].
Enhanced inflammation was also observed in apoE4
mice brain and in mice microglia following LPS stimula-
tion relative to apoE3 [72, 73] with the opposite effects
shown for astroglia, indicating cell-specific effects. Fur-
thermore, an isoform-specific difference in microglial NO
production has been reported, in which apoE4 produce
greater NO amounts than apoE3 mice [75, 76].
The exact molecular mechanism by which apoE modu-
lates LPS-induced brain inflammation brain remains to be
elucidated. However, it was shown that a peptide containing
the receptor-binding region (residues 133149) was
enough to suppress inflammation [70]. Of note, is the fact
that this peptide is almost the same peptide that Pham et al.
[59] demonstrated to be responsible for the antioxidant
properties.
ApoE has been postulated to influence different signal-
ling pathways. Ophir et al. [72] demonstrated that the genes
that were most differentially expressed in apoE4 compared
to apoE3 were significantly enriched in nuclear factor jB
(NFjB) response elements. In addition, it was shown that
microglial NFjB activation was greater in apoE4 mice. On
the other hand, Maezawa et al. [73, 74] support the hypoth-
esis that apoE genotype-mediated effects in microglia are
p38MAPK dependent.
5.2 Inflammation in relation to CVD
The macrophage innate immune response is a key feature
of atherosclerosis. We tested the hypothesis that apoE4 was
associated with enhanced inflammation by using a murine
monocyte-macrophage cell line (RAW 264.7) stably trans-
fected to express equal amounts of apoE3 or apoE4. Indeed,
we found cytokine disequilibrium between the pro- and
anti-inflammatory cytokines. LPS-stimulated macrophages
secreting apoE4 showed increased TNFa, but decreased
IL10 in comparison to apoE3 macrophages [77]. In addi-
tion, increased NFjB transactivation in apoE4-cells was
evident, suggesting a prominent role of this transcription
factor pathway in mediating apoE genotype differences in
response. We also demonstrated [77] (Table 4) that the
expression of heme oxygenase-1 (HO-1), a stress response
anti-inflammatory protein, was increased in apoE4 macro-
phages, suggesting that its increased synthesis in apoE4
cells could be a response to a pro-inflammatory status pro-
duced to counteract in part the detrimental effects associ-
ated with increased cytokine production. At the same time,
Tsoi and co-workers [78] published a study with a similar
cell culture model (J774A.1) and showed that apoE4 and
apoE2 macrophages produced higher amounts of TNFa and
IL6. In addition, it was shown that these effects were partly
mediated by modulation of the ERK1/2 MAP-kinase sig-
nalling pathway, suggesting that apoE isoforms differen-
tially modulates the activation of parallel signalling cas-
cades triggered by LPS.
The precise mechanisms by which apoE isoforms alter
the innate immune response remain undefined. However, as
oxidative stress is a known modulator of this response it is
likely that the differential antioxidant capacity of the apoE
isoforms could be in part responsible for the differential
modulation of the redox-sensitive transcription pathways
such as NFjB and MAP kinases. Alternatively, apoE could
act through binding to cell surface receptors. It has been
postulated that apoE immunomodulatory properties could
be mediated by the LDL receptor-related protein (LRP),
with consequent mobilisation of intracellular calcium [79].
However, the affinity to this receptor has not been proven to
differ among the apoE isoforms [80].
A weakness of all of this evidence is that in almost all the
studies, LPS was used as an inflammation inducer.
Although this is a commonly used approach to investigate
innate immune response, and there are data that support a
139
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Table 4. Continued
Author, year Model Species Parameter Outcome
Tziakas et al. 2006 [83] Acute coronary syn-
drome and chronic sta-
ble angina patients
H IL10 (anti-inflammatory cytokine)
CRP
E3/E4 a E3/E3 a E2/E3
E3/E4 A E3/E3
Tsoi et al. 2007 [78] Mouse J774A.1 perito-
neal macrophages ex-
pressing apoE2,
apoE3, apoE4
CC (M) TNF-a, IL6 expression
ERK1/2 activity
–E3a E2=E4
–E3a E2 = E4
Jofre-Monseny et al. 2007
[77]
Mouse RAW 264.7
macrophages express-
ing apoE3 and apoE4
CC (M) TNF-a
IL10
NFkB transactivation
HO-1
–E4A E3
–E3A E4
–E4A E3
–E4A E3
H, human; M, mouse; R, rat; CC, cell culture.
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
role of LPS and its receptor, Toll-like receptor 4 (TLR4), in
the process of atherogenesis [81]; the relevance of these
models for the pathogenesis of AD and CVD needs to be
verified. It would be of great interest to reveal whether these
effects are also observed with more physiological inflam-
mation inducers such as ox-LDL.
Nevertheless, limited data in humans show an effect of
apoE genotype on pro- and anti-inflammatory cytokines
independently of any exogenous source of experimental
inflammation inducer. In a study of patients undergoing car-
diopulmonary bypass surgery, a process that induces a tran-
sient rise in pro-inflammatory cytokines mainly released by
activated monocytes, it was shown that apoE4 was associ-
ated with increased IL8 and TNFa [82]. In patients with
acute coronary syndrome, significant lower levels of the
anti-inflammatory IL10 were observed in e4 carriers, with
the same trend evident in chronic stable angina patients
[83]. This is in accordance with our findings in macro-
phages, supporting the hypothesis of an inflammatory
imbalance between the pro- and anti-inflammatory cyto-
kines in apoE4 carriers. The secretion of other mediators of
inflammation that participate in the adhesion of inflamma-
tory cells to the vascular surface, such as vascular cell adhe-
sion molecule-1 (VCAM-1), were found to be modified by
the apoE genotype (E4 A E3 A E2) (Minihane et al., unpub-
lished results). Conversely, VCAM-1, intracellular adhe-
sion molecule-1 and E-selectin were not altered by the
apoE genotype in a study with low-HDL and normolipi-
demic subjects [84]. Other established indicators of sys-
temic inflammation, fibrinogen and white cell count were
not related to the apoE genotype [85].
5.3 ApoE and C-reactive protein
The levels of C-reactive protein (CRP) have been robustly
associated with apoE genotype with apoE4 individuals pre-
senting with lower and E2 carriers with higher CRP levels
than E3/E3 individuals [84 87]. In addition, we observed
the same association in targeted replacement mice express-
ing apoE3 and apoE4 (Jofre-Monseny, unpublished data).
At present the mechanisms responsible for this association
remain unclear. CRP is a product of hepatic stimulation by
“messenger cytokines” such as IL6. Currently, it is consid-
ered the most robust inflammatory marker of CVD risk.
[88]. At present, it seems contradictory that apoE4 is asso-
ciated with increased brain and macrophage inflammation,
and increased CVD, while at the same time is related to low
levels of CRP. Mrz and associates [85] suggest that the
metabolism of CRP could be related to the mevalonate/cho-
lesterol synthetic pathway, which may be down-regulated in
apoE4 carriers in response to altered lipoprotein metabo-
lism and hepatic uptake. Whatever the mechanism, it may
be necessary to re-evaluate the meaning of CRP as a predic-
tor marker according to the apoE genotype. If apoE geno-
type modulates CRP synthesis by a cytokine-independent
mechanism, the CVD risk could be underestimated if CRP
was used as a prediction factor in apoE4 carriers. However,
if CRP is not just a surrogate marker, but also a causal factor
and exerts direct functions in the development of athero-
sclerosis [89], the detrimental effects of apoE4 might be
partly counteracted by lower levels of CRP. In addition, it is
possible that the increased CRP levels observed in apoE2-
carriers partly counteract the observed beneficial effects
associated to apoE2 isoform (such as lower cholesterol lev-
els [4] and better antioxidant properties [43]), which may
explain the observation of no CVD-risk reduction consis-
tently reported in e2 carriers [3].
6 Is it meaningful to genotype for apoE?
The e4 allele, which is carried by 25% of Caucasian popu-
lations, is associated with a 4050% increased risk of CVD
[3]. As CVD remains the main source of morbidity and
mortality in Westernised societies, a reduction in the CVD
burden associated with an apoE4 genotype would be of
wide public health benefit. Although not fully resolved,
numerous studies have reported on the impact of apoE gen-
otype on the responsiveness of CVD biomarkers to environ-
mental (diet, smoking status, alcohol intake, exercise)
change, with e4 carriers being particularly responsive. This
indicates the potential of altered lifestyle as a means of
reducing or negating the increased risk of CVD in those
identified as having an apoE4 genotype.
6.1 Smoking status
As mentioned before, apoE4 carriers are more sensitive to
the detrimental effects of tobacco smoking [51, 53, 90]
6.2 Alcohol drinking
There are limited data showing that the effects of alcohol on
plasma lipids are modulated by the apoE genotype, yet
inconsistent alcohol-apoE genotype-CVD phenotype asso-
ciations have been reported, e.g., it was found [91] that in
male non-drinkers, no effects of apoE genotype on LDL-
cholesterol (LDL-C) levels could be observed, while in
drinkers, the apoE genotype was associated with different
LDL-C levels with apoE2 a apoE3 a apoE4. In contrast, it
was reported [92] that in apoE2, alcohol consumption
increased LDL-C, whereas in apoE4, it decreased LDL-C.
Furthermore, the increase in HDL associated with alcohol
appears to be stronger in subjects without the apoE4 allele
than in those with the apoE4 [93]. However, no interaction
between apoE4 and drinking was found on the prevalence
of carotid atherosclerosis [90]. In addition, a prospective
population-based study concluded that the risk of dementia
increased with increasing alcohol consumption only in
apoE4 carriers [94].
140
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2008, 52, 131 145
6.3 Physical activity
Beneficial effects of physical activity on HDL-C levels were
observed in apoE4 men but not in women. Men carrying the
e4 allele had lower HDL-C levels if sedentary and higher
HDL-C levels if physically active than apoE3 individuals,
with the opposite effects evident in apoE2 carriers [92]. A
recent study with older women suggested that aerobic physi-
cal activity could have a beneficial impact on cognitive per-
formance particularly in apoE4 homozygotes [95].
6.4 Saturated fat, total fat and cholesterol intake
In general apoE4 individuals have been shown to be the
most responsive to reduced saturated and total fat, and cho-
lesterol intake (for review see [4])
6.5 Antioxidant supply
Given that apoE4 is associated with increased oxidative
stress, it has been hypothesised that apoE4 carriers could
potentially benefit from antioxidant supplementation [96].
Vitamin C supplementation (60 mg/day) was able to down-
regulate monocyte-derived pro-inflammatory mediators in
apoE4 individuals who smoked. In this study, apoE4-non-
smokers were much less responsive than apoE4-smokers
[97]. However, this study only included apoE4 car riers. The
impact of apoE genotype on the responsiveness of oxidative
status and inflammatory markers to antioxidant supplemen-
tation in E3 versus E4 in a non-smoking group has never
been investigated. We investigated the effects of a-toco-
pherol supplementation in apoE3 and apoE4 transgenic
mice. Our data suggest that the transport of a-tocopherol
into the tissues may be altered by the apoE genotype, in
which apoE4 show decreased a-tocopherol levels in tissues
and increased levels in plasma. These data are supported by
other reports showing increased plasma concentrations of
a-tocopherol in apoE4 carriers [98, 99].
6.6 Caloric restriction
Caloric restriction has been shown to be beneficial in dis-
eases associated with oxidative stress. In apoE null mice,
caloric restriction could retard atherosclerosis through a
mechanism that was independent of plasma cholesterol lev-
els [100]. We propose that this could be a further potential
measure by which apoE4 individuals could reduce the
increased CVD burden.
6.7 ApoE genotype, environment interactions
To date, there is not sufficient consistent information to
advocate specific dietary recommendations or pharmaceut-
ical therapies to help negate the impact of an apoE4 geno-
type [92]. Although these data are highly suggestive of diet-
genotype interactions, with strong indication that in apoE4
carriers such lifestyle approaches as of avoiding smoking,
increasing physical activity and antioxidant intake and
reducing alcohol, total fat and saturated fat intake could in
part negate the apoE4-mediated increases in CVD risk, the
data are inconsistent. This may be in large part attributable
to the fact that most of the evidence considered, to date, is
derived from observational or intervention trials in which
inaccurate assessment of lifestyle, in particular dietary
intake, and small group number in the rare allele groups
associated with retrospective genotyping has led to incon-
sistent findings.
Furthermore, although less information is currently
available, it is likely that apoE4-AD risk associations are
also sensitive to environmental factors. However, research
in this area is in its relative infancy.
7 Conclusions
ApoE polymor phism is associated with many diseases that
apparently have different origins. However, two important
hallmarks of these diseases are oxidative stress and inflam-
mation. There is increasing evidence demonstrating that
apoE4 is associated with increased oxidative stress and
inflammation, which is likely to in part mediate the effect
of genotype on AD and CVD burden. At present our under-
standing of the strength of association between apoE geno-
type and AD and CVD is relatively well developed, with
growing evidence that it is modifiable by lifestyle changes.
However, before a more widespread use of apoE gene
profiling can be used as a predictive tool to help identify
individuals at above-average risk for these two conditions,
clear guidelines regarding which lifestyle changes can be
adopted to help negate the increased risk in E4 carriers need
to be available.
Although at present a developing body of evidence is
becoming available regarding lifestyle-genotyping interac-
tions in the area of CVD, no such information is available
for AD. Larger intervention trials, using prospective recruit-
ment of study participants are needed to gain a fuller under-
standing of apoE genotype-lifestyle-CVD/AD risk associa-
tions and to gain an understanding of the mechanisms
underlying these interactions.
This work was supported by grants of the German Ministry
of Education and Science (BMBF 0313856A), the Danone
foundation and the ISFE foundation.
The authors have declared no conflict of interest.
8 References
[1] WHO, Cardiovascular diseases, World Health Organization.
2007, Fact sheet 317.
141
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
[2] Chicot, J. V., Rajkumar, S., Tanyakitpisal., P., Chandra, V.,
Alzheimer's disease: Of emerging Importance, WHO
Regional Health Forum 2002, 6, 39 48.
[3] Song, Y., Stampfer, M. J., Liu, S., Meta-analysis: Apolipopro-
tein E genotypes and risk for coronary heart disease. Ann.
Intern. Med. 2004, 141, 137147.
[4] Minihane, A. M., Jofre-Monseny, L., Olano-Martin, E., Rim-
bach, G., ApoE genotype, cardiovascular risk and responsive-
ness to dietar y fat manipulation. Proc. Nutr. Soc. 2007, 66,
183197.
[5] Basu, S. K., Brown, M. S., Ho, Y. K., Havel, R. J., Goldstein,
J. L., Mouse macrophages synthesize and secrete a protein
resembling apolipoprotein E. Proc. Natl. Acad. Sci. USA
1981, 78, 75457549.
[6] Kayden, H. J., Maschio, F., Traber, M. G., The secretion of
apolipoprotein E by human monocyte-derived macrophages.
Arch. Biochem. Biophys. 1985, 239, 388395.
[7] Newman, T. C., Dawson, P. A., Rudel, L. L., Williams, D. L.,
Quantitation of apolipoprotein E mRNA in the liver and
peripheral tissues of nonhuman primates. J. Biol. Chem.
1985, 260, 24522457.
[8] Lovestone, S., Anderton, B. H., Har tley, C., Jensen, T. G., Jor-
gensen, A. L., The intracellular fate of apolipoprotein E is tau
dependent and apoe allele-specific. Neuroreport 1996, 7,
10051008.
[9] Ladu, M. J., Reardon, C., Van Eldik, L., Fagan, A. M., et al.,
Lipoproteins in the central nervous system. Ann. N. Y. Acad.
Sci. 2000, 903, 167 175.
[10] Poirier, J., Apolipoprotein E in animal models of CNS injury
and in Alzheimer's disease. Trends Neurosci. 1994, 17, 525
530.
[11] Riddell, D. R., Graham, A., Owen, J. S., Apolipoprotein E
inhibits platelet aggregation through the L-arginine:nitric
oxide pathway. Implications for vascular disease. J. Biol.
Chem. 1997, 272, 89 95.
[12] Bellosta, S., Mahley, R. W., Sanan, D. A., Murata, J., et al.,
Macrophage-specific expression of human apolipoprotein E
reduces atherosclerosis in hypercholesterolemic apolipopro-
tein E-null mice. J. Clin. Invest. 1995, 96, 2170 2179.
[13] Shimano, H., Ohsuga, J., Shimada, M., Namba, Y., et al.,
Inhibition of diet-induced atheroma formation in transgenic
mice expressing apolipoprotein E in the arterial wall. J. Clin.
Invest. 1995, 95, 469 476.
[14] Stannard, A. K., Riddell, D. R., Sacre, S. M., Tagalakis, A. D.,
et al., Cell-derived apolipoprotein E (ApoE) particles inhibit
vascular cell adhesion molecule-1 (VCAM-1) expression in
human endothelial cells. J. Biol. Chem. 2001, 276, 46011
46016.
[15] Zeleny, M., Swertfeger, D. K., Weisgraber, K. H., Hui, D. Y.,
Distinct apolipoprotein E isoform preference for inhibition of
smooth muscle cell migration and proliferation. Biochemistry
2002, 41, 1182011823.
[16] Rall, S. C. Jr., Weisgraber, K. H., Mahley, R. W., Human apo-
lipoprotein E. The complete amino acid sequence. J. Biol.
Chem. 1982, 257, 4171 4178.
[17] Weisgraber, K. H., Rall, S. C. Jr., Mahley, R. W., Human E
apoprotein heterogeneity. Cysteine-arginine interchanges in
the amino acid sequence of the apo-E isoforms. J. Biol.
Chem. 1981, 256, 9077 9083.
[18] Weisgraber, K. H., Innerarity, T. L., Mahley, R. W., Abnormal
lipoprotein receptor-binding activity of the human E apopro-
tein due to cysteine-arginine interchange at a single site. J.
Biol. Chem. 1982, 257, 25182521.
[19] Innerarity, T. L., Weisgraber, K. H., Arnold, K. S., Rall, S. C.
Jr., Mahley, R. W., Normalization of receptor binding of apo-
lipoprotein E2. Evidence for modulation of the binding site
conformation. J. Biol. Chem. 1984, 259, 7261 7267.
[20] Hatters, D. M., Peters-Libeu, C. A., Weisgraber, K. H., Apoli-
poprotein E structure: Insights into function. Trends Biochem.
Sci. 2006, 31, 445 454.
[21] Dong, L. M., Wilson, C., Wardell, M. R., Simmons, T., et al.,
Human apolipoprotein E. Role of arginine 61 in mediating
the lipoprotein preferences of the E3 and E4 isoforms. J. Biol.
Chem. 1994, 269, 22358 22365.
[22] Giassakis, G., Veletza, S., Papanas, N., Heliopoulos, I., Piper-
idou, H., Apolipoprotein E and first-ever ischaemic stroke in
Greek hospitalized patients. J. Int. Med. Res. 2007, 35, 127
133.
[23] Kesseler, C., Spitzer, C., Stauske, D., Mende, S., et al., The
Apolipoprotein E and ß-fibrinogen G/A-455 gene polymor-
phisms are associated with ischemic stroke involving large-
vessel disease. Arterioscler. Thromb. Vasc. Biol. 1997, 17,
22802884.
[24] Lewis, S. J., Brunner, E. J., Methodological problems in
genetic association studies of longevity-The apolipoprotein E
gene as an example. Int. J. Epidemiol. 2004, 33, 962970.
[25] Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., Tanzi,
R. E., Systematic meta-analyses of Alzheimer disease genetic
association studies: The AlzGene database. Nat. Genet. 2007,
39, 17 23.
[26] Teasdale, G. M., Nicoll, J. A., Murray, G., Fiddes, M., Associ-
ation of apolipoprotein E polymorphism with outcome after
head injury. Lancet 1997, 350, 1069 1071.
[27] Friedman, G., Froom, P., Sazbon, L., Grinblatt, I., et al., Apo-
lipoprotein E-epsilon4 genotype predicts a poor outcome in
survivors of traumatic brain injury. Neurology 1999, 52,
244248.
[28] Lelis, R. G., Krieger, J. E., Pereira, A. C., Schmidt, A. P., et
al., Apolipoprotein E4 genotype increases the risk of postop-
erative cognitive dysfunction in patients undergoing coronary
artery bypass graft surgery. J. Cardiovasc. Surg. (Torino)
2006, 47, 451456.
[29] Newman, M. F., Croughwell, N. D., Blumenthal, J. A., Lowry,
E., et al., Predictors of cognitive decline after cardiac opera-
tion. Ann. Thorac. Surg. 1995, 59, 13261330.
[30] Pinholt, M., Frederiksen, J. L., Christiansen, M., The associa-
tion between apolipoprotein E and multiple sclerosis. Eur. J.
Neurol. 2006, 13, 573580.
[31] Corder, E. H., Robertson, K., Lannfelt, L., Bogdanovic, N., et
al., HIV-infected subjects with the E4 allele for APOE have
excess dementia and peripheral neuropathy. Nat. Med. 1998,
4, 1182 1184.
[32] Campalani, E., Allen, M. H., Fairhurst, D., Young, H. S., et
al., Apolipoprotein E gene polymorphisms are associated
with psoriasis but do not determine disease response to acitre-
tin. Br. J. Dermatol. 2006, 154, 345352.
[33] Economou-Petersen, E., Aessopos, A., Kladi, A., Flevari, P.,
et al., Apolipoprotein E epsilon4 allele as a genetic risk factor
for left ventricular failure in homozygous beta-thalassemia.
Blood 1998, 92, 3455 3459.
[34] Thakkinstian, A., Bowe, S., McEvoy, M., Smith, W., Attia, J.,
Association between apolipoprotein E polymor phisms and
age-related macular degeneration: A HuGE review and meta-
analysis. Am. J. Epidemiol. 2006, 164, 813822.
142
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2008, 52, 131 145
[35] Friedman, D. A., Lukiw, W. J., Hill, J. M., Apolipoprotein E
epsilon4 offers protection against age-related macular degen-
eration. Med. Hypotheses 2007, 68, 10471055.
[36] Oria, R. B., Patrick, P. D., Blackman, J. A., Lima, A. A., Guer-
rant, R. L., Role of apolipoprotein E4 in protecting children
against early childhood diarrhea outcomes and implications
for later development. Med. Hypotheses 2007, 68, 1099
1107.
[37] Oria, R. B., Patrick, P. D., Zhang, H., Lorntz, B., et al., ApoE4
protects the cognitive development in children with heavy
diarrhea burdens in Northeast Brazil. Pediatr. Res. 2005, 57,
310316.
[38] Wozniak, M. A., Itzhaki, R. F., Faragher, E. B., James, M. W.
et al., Apolipoprotein E-epsilon 4 protects against severe liver
disease caused by hepatitis C virus. Hepatology 2002, 36,
456463.
[39] Hayek, T., Oiknine, J., Brook, J. G., Aviram, M., Increased
plasma and lipoprotein lipid peroxidation in apo E-deficient
mice. Biochem. Biophys. Res. Commun. 1994, 201, 1567
1574.
[40] Pratico, D., Tangirala, R. K., Rader, D. J., Rokach, J., FitzGer-
ald, G. A., Vitamin E suppresses isoprostane generation in
vivo and reduces atherosclerosis in ApoE-deficient mice.
Nat. Med. 1998, 4, 11891192.
[41] Tangirala, R. K., Pratico, D., FitzGerald, G. A., Chun, S., et
al., Reduction of isoprostanes and regression of advanced
atherosclerosis by apolipoprotein E. J. Biol. Chem. 2001,
276, 261 266.
[42] Kitagawa, K., Matsumoto, M., Kuwabara, K., Takasawa, K.
et al., Protective effect of apolipoprotein E against ischemic
neuronal injury is mediated through antioxidant action. J.
Neurosci. Res. 2002, 68, 226232.
[43] Miyata, M., Smith, J. D., Apolipoprotein E allele-specific
antioxidant activity and effects on cytotoxicity by oxidative
insults and beta-amyloid peptides. Nat. Genet. 1996, 14, 55
61.
[44] Ramassamy, C., Averill, D., Beffert, U., Bastianetto, S., et al.,
Oxidative damage and protection by antioxidants in the fron-
tal cortex of Alzheimer's disease is related to the apolipopro-
tein E genotype. Free Radic. Biol. Med. 1999, 27, 544 553.
[45] Ramassamy, C., Averill, D., Beffert, U., Theroux, L., et al.,
Oxidative insults are associated with apolipoprotein E geno-
type in Alzheimer's disease brain. Neurobiol. Dis. 2000, 7,
2337.
[46] Tamaoka, A., Miyatake, F., Matsuno, S., Ishii, K., et al., Apo-
lipoprotein E allele-dependent antioxidant activity in brains
with Alzheimer's disease. Neurology 2000, 54, 23192321.
[47] Ihara, Y., Hayabara, T., Sasaki, K., Kawada, R., et al., Rela-
tionship between oxidative stress and apoE phenotype in Alz-
heimer's disease. Acta Neurol. Scand. 2000, 102, 346349.
[48] Fernandes, M. A., Proenca, M. T., Nogueira, A. J., Grazina,
M. M. et al., Influence of apolipoprotein E genotype on blood
redox status of Alzheimer's disease patients. Int. J. Mol. Med.
1999, 4, 179186.
[49] Lauderback, C. M., Kanski, J., Hackett, J. M., Maeda, N., et
al., Apolipoprotein E modulates Alzheimer's Abeta(1-42)-
induced oxidative damage to synaptosomes in an allele-spe-
cific manner. Brain Res. 2002, 924, 9097.
[50] Yao, J., Petanceska, S. S., Montine, T. J., Holtzman, D. M., et
al., Aging, gender and APOE isotype modulate metabolism
of Alzheimer's Abeta peptides and F-isoprostanes in the
absence of detectable amyloid deposits. J. Neurochem. 2004,
90, 1011 1018.
[51] Humphries, S. E., Talmud, P. J., Hawe, E., Bolla, M., et al.,
Apolipoprotein E4 and coronary heart disease in middle-aged
men who smoke: A prospective study. Lancet 2001, 358,
115119.
[52] Lahoz, C., Schaefer, E. J., Cupples, L. A., Wilson, P. W., et
al., Apolipoprotein E genotype and cardiovascular disease in
the Framingham Heart Study. Atherosclerosis 2001, 154,
529537.
[53] Talmud, P. J., Stephens, J. W., Hawe, E., Demissie, S., et al.,
The significant increase in cardiovascular disease risk in
ApoE4 carriers is evident only in men who smoke: Potential
relationship between reduced antioxidant status and ApoE4.
Ann. Hum. Genet. 2005, 69, 613622.
[54] Talmud, P. J., Gene-environment interaction and its impact on
coronary heart disease risk. Nutr. Metab. Cardiovasc. Dis.
2007, 17, 148152.
[55] Dietrich, M., Hua, Y., Block, G., Olano, E., et al., Associa-
tions between apolipoprotein E genotype and circulating F2-
isoprostane levels in humans. Lipids 2005, 40, 329334.
[56] Tsuda, M., Sanada, M., Nakagawa, H., Kodama, I., et al.,
Phenotype of apolipoprotein E influences the lipid metabolic
response of postmenopausal women to hormone replacement
therapy. Maturitas 2001, 38, 297304.
[57] Jofre-Monseny, L., de Pascual-Teresa, S., Plonka, E., Huebbe,
P. , et al., Differential effects of apolipoprotein E3 and E4 on
markers of oxidative status in macrophages. Br. J. Nutr. 2007,
97, 864 871.
[58] Mabile, L., Lefebvre, C., Lavigne, J., Boulet, L., et al.,
Secreted apolipoprotein E reduces macrophage-mediated
LDL oxidation in an isoform-dependent way. J. Cell Bio-
chem. 2003, 90, 766776.
[59] Pham, T., Kodvawala, A., Hui, D. Y., The receptor binding
domain of apolipoprotein e is responsible for its antioxidant
activity. Biochemistry 2005, 44, 75777582.
[60] Pedersen, W. A., Chan, S. L., Mattson, M. P., A mechanism
for the neuroprotective effect of apolipoprotein E: isoform-
specific modification by the lipid peroxidation product 4-
hydroxynonenal. J. Neurochem. 2000, 74, 14261433.
[61] Pepe, M. G., Curtiss, L. K., Apolipoprotein E is a biologically
active constituent of the normal immunoregulatory lipopro-
tein, LDL-In. J. Immunol. 1986, 136, 37163723.
[62] Kelly, M. E., Clay, M. A., Mistry, M. J., Hsieh-Li, H. M., Har-
mony, J. A., Apolipoprotein E inhibition of proliferation of
mitogen-activated T lymphocytes: Production of interleukin
2 with reduced biological activity. Cell. Immunol. 1994, 159,
124139.
[63] Mistry, M. J., Clay, M. A., Kelly, M. E., Steiner, M. A., Har-
mony, J. A., Apolipoprotein E restricts interleukin-dependent
T lymphocyte proliferation at the G1A/G1B boundary. Cell.
Immunol. 1995, 160, 14 23.
[64] Roselaar, S. E., Daugherty, A., Apolipoprotein E-deficient
mice have impaired innate immune responses to Listeria
monocytogenes in vivo. J. Lipid Res. 1998, 39, 17401743.
[65] de Bont, N., Netea, M. G., Demacker, P. N., Verschueren, I.,
et al., Apolipoprotein E knock-out mice are highly suscepti-
ble to endotoxemia and Klebsiella pneumoniae infection. J.
Lipid Res. 1999, 40, 680685.
[66] Van Oosten, M., Rensen, P. C., Van Amersfoort, E. S., Van
Eck, M. et al., Apolipoprotein E protects against bacterial lip-
opolysaccharide-induced lethality. A new therapeutic
approach to treat gram-negative sepsis. J. Biol. Chem. 2001,
276, 8820 8824.
143
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
L. Jofre-Monseny et al. Mol. Nutr. Food Res. 2008, 52, 131 145
[67] Laskowitz, D. T., Goel, S., Bennett, E. R., Matthew, W. D.,
Apolipoprotein E suppresses glial cell secretion of TNF
alpha. J. Neuroimmunol. 1997, 76, 70 74.
[68] Egensperger, R., Kosel, S., von Eitzen, U., Graeber, M. B.,
Microglial activation in Alzheimer disease: Association with
ApoE genotype. Brain Pathol. 1998, 8, 439 447.
[69] Lynch, J. R., Morgan, D., Mance, J., Matthew, W. D., Lasko-
witz, D. T., Apolipoprotein E modulates glial activation and
the endogenous central ner vous system inflammatory
response. J. Neuroimmunol. 2001, 114, 107113.
[70] Lynch, J. R., Tang, W., Wang, H., Vitek, M. P., et al., APOE
genotype and an ApoE-mimetic peptide modify the systemic
and central nervous system inflammatory response. J. Biol.
Chem. 2003, 278, 48529 48533.
[71] Guo, L., LaDu, M. J., Van Eldik, L. J., A dual role for apolipo-
protein e in neuroinflammation: Anti- and pro-inflammatory
activity. J. Mol. Neurosci. 2004, 23, 205212.
[72] Ophir, G., Amariglio, N., Jacob-Hirsch, J., Elkon, R., et al.,
Apolipoprotein E4 enhances brain inflammation by modula-
tion of the NF-kappaB signaling cascade. Neurobiol. Dis.
2005, 20, 709718.
[73] Maezawa, I., Nivison, M., Montine, K. S., Maeda, N., Mon-
tine, T. J., Neurotoxicity from innate immune response is
greatest with targeted replacement of E4 allele of apolipopro-
tein E gene and is mediated by microglial p38MAPK. FASEB
J. 2006, 20, 797799.
[74] Maezawa, I., Maeda, N., Montine, T. J., Montine, K. S., Apo-
lipoprotein E-specific innate immune response in astrocytes
from targeted replacement mice. J. Neuroinflamm. 2006, 3,
10.
[75] Colton, C. A., Brown, C. M., Czapiga, M., Vitek, M. P., Apo-
lipoprotein-E allele-specific regulation of nitric oxide pro-
duction. Ann. N. Y. Acad. Sci. 2002, 962, 212 225.
[76] Colton, C. A., Brown, C. M., Cook, D., Needham, L. K., et
al., APOE and the regulation of microglial nitric oxide pro-
duction: a link between genetic risk and oxidative stress. Neu-
robiol. Aging 2002, 23, 777785.
[77] Jofre-Monseny, L., Loboda, A., Wagner, A. E., Huebbe, P., et
al., Effects of apoE genotype on macrophage inflammation
and heme oxygenase-1 expression. Biochem. Biophys. Res.
Commun. 2007, 357, 319 324.
[78] Tsoi, L. M., Wong, K. Y., Liu, Y. M., Ho, Y. Y., Apoprotein E
isoform-dependent expression and secretion of pro-inflam-
matory cytokines TNF-alpha and IL-6 in macrophages. Arch.
Biochem. Biophys. 2007, 460, 33 40.
[79] Misra, U. K., Adlakha, C. L., Gawdi, G., McMillian, M. K., et
al., Apolipoprotein E and mimetic peptide initiate a calcium-
dependent signaling response in macrophages. J. Leukoc.
Biol. 2001, 70, 677 683.
[80] Ruiz, J., Kouiavskaia, D., Migliorini, M., Robinson, S., et al.,
The apoE isoform binding properties of the VLDL receptor
reveal marked differences from LRP and the LDL receptor. J.
Lipid Res. 2005, 46, 17211731.
[81] Michelsen, K. S., Doherty, T. M., Shah, P. K., Arditi, M., TLR
signaling: An emerging bridge from innate immunity to athe-
rogenesis. J. Immunol. 2004, 173, 59015907.
[82] Drabe, N., Zund, G., Grunenfelder, J., Sprenger, M., et al.,
Genetic predisposition in patients undergoing cardiopulmo-
nary bypass surgery is associated with an increase of inflam-
matory cytokines. Eur. J. Cardiothorac. Surg. 2001, 20, 609
613.
[83] Tziakas, D. N., Chalikias, G. K., Antonoglou, C. O., Veletza,
S. et al., Apolipoprotein E genotype and circulating interleu-
kin-10 levels in patients with stable and unstable coronary
artery disease. J. Am. Coll. Cardiol. 2006, 48, 24712481.
[84] Kahri, J., Soro-Paavonen, A., Ehnholm, C., Taskinen, M. R.,
ApoE polymorphism is associated with C-reactive protein in
low-HDL family members and in normolipidemic subjects.
Mediators Inflamm. 2006, 2006, 12587.
[85] Mrz, W., Scharnagl, H., Hoffmann, M. M., Boehm, B. O.,
Winkelmann, B. R., The apolipoprotein E polymorphism is
associated with circulating C-reactive protein (the Ludwig-
shafen risk and cardiovascular health study). Eur. Heart J.
2004, 25, 21092119.
[86] Manttari, M., Manninen, V., Palosuo, T., Ehnholm, C., Apoli-
poprotein E polymorphism and C-reactive protein in dyslipi-
demic middle-aged men. Atherosclerosis 2001, 156, 237
238.
[87] Judson, R., Brain, C., Dain, B., Windemuth, A., et al.,New
and confirmatory evidence of an association between APOE
genotype and baseline C-reactive protein in dyslipidemic
individuals. Atherosclerosis 2004, 177, 345351.
[88] Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J.
L., et al., Markers of inflammation and cardiovascular dis-
ease: Application to clinical and public health practice: A
statement for healthcare professionals from the Centers for
Disease Control and Prevention and the American Heart
Association. Circulation 2003, 107, 499 511.
[89] Paffen, E., DeMaat, M. P., C-reactive protein in atherosclero-
sis: A causal factor? Cardiovasc. Res. 2006, 71, 30 39.
[90] Djousse, L., Myers, R. H., Province, M. A., Hunt, S. C., et al.,
Influence of apolipoprotein E, smoking, and alcohol intake
on carotid atherosclerosis: National Heart, Lung, and Blood
Institute Family Heart Study. Stroke 2002, 33, 13571361.
[91] Corella, D., Tucker, K., Lahoz, C., Coltell, O., et al., Alcohol
drinking determines the effect of the APOE locus on LDL-
cholesterol concentrations in men: the Framingham Off-
spring Study. Am. J. Clin. Nutr. 2001, 73, 736745.
[92] Corella, D., Guillen, M., Saiz, C., Portoles, O., et al., Environ-
mental factors modulate the effect of the APOE genetic poly-
morphism on plasma lipid concentrations: Ecogenetic studies
in a Mediterranean Spanish population. Metabolism 2001,
50, 936 944.
[93] Djousse, L., Pankow, J. S., Arnett, D. K., Eckfeldt, J. H., et
al., Apolipoprotein E polymorphism modifies the alcohol-
HDL association observed in the National Heart, Lung, and
Blood Institute Family Heart Study. Am. J. Clin. Nutr. 2004,
80, 1639 1644.
[94] Anttila, T., Helkala, E. L., Viitanen, M., Kareholt, I., et al.,
Alcohol drinking in middle age and subsequent risk of mild
cognitive impairment and dementia in old age: A prospective
population based study. BMJ 2004, 329, 539.
[95] Etnier, J. L., Caselli, R. J., Reiman, E. M., Alexander, G. E.,
et al., Cognitive performance in older women relative to
ApoE-epsilon4 genotype and aerobic fitness. Med. Sci.
Sports Exerc. 2007, 39, 199 207.
[96] Peroutka, S. J., Dreon, D. M., The value of genotyping for
apolipoprotein E alleles in relation to vitamin E supplementa-
tion. Eur. J. Pharmacol. 2000, 410, 161163.
[97] Majewicz, J., Rimbach, G., Proteggente, A. R., Lodge, J. K.,
et al., Dietary vitamin C down-regulates inflammatory gene
expression in apoE4 smokers. Biochem. Biophys. Res. Com-
mun. 2005, 338, 951 955.
144
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2008, 52, 131 145
[98] Lodge, J. K., Hall, W. L., Jeanes, Y. M., Proteggente, A. R.,
Physiological factors influencing vitamin E biokinetics.
Ann. N. Y. Acad. Sci. 2004, 1031, 6073.
[99] Gomez-Coronado, D., Entrala, A., Alvarez, J. J., Ortega, H.,
et al., Influence of apolipoprotein E polymorphism on
plasma vitamin A and vitamin E levels. Eur. J. Clin. Invest.
2002, 32, 251258.
[100] Guo, Z., Mitchell-Raymundo, F., Yang, H., Ikeno, Y., et al.,
Dietary restriction reduces atherosclerosis and oxidative
stress in the aorta of apolipoprotein E-deficient mice. Mech.
Ageing Dev. 2002, 123, 11211131.
[101] Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schme-
chel, D. E., et al., Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families.
Science 1993, 261, 921923.
[102] Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., et al.,
Apolipoprotein E polymorphism and Alzheimer's disease.
Lancet 1993, 342, 697 699.
[103] Wilson, P. W., Schaefer, E. J., Larson, M. G., Ordovas, J. M.,
Apolipoprotein E alleles and risk of coronary disease. A
meta-analysis. Arterioscler. Thromb. Vasc. Biol. 1996, 16,
12501255.
[104] Jolivalt, C., Leininger-Muller, B., Bertrand, P., Herber, R., et
al., Differential oxidation of apolipoprotein E isoforms and
interaction with phospholipids. Free Radic. Biol. Med. 2000,
28, 129 140.
[105] Tsuda, M., Sanada, M., Higashi, Y., Hara, Y., et al., Apolipo-
protein E phenotype affects the malondialdehyde-modified
LDL concentration and forearm endothelial function in post-
menopausal women. Clin. Endocrinol. (Oxf). 2004, 61,
619625.
[106] Stohr, J., Schindler, G., Rothe, G., Schmitz, G., Enhanced
upregulation of the Fc gamma receptor IIIa (CD16a) during
in vitro differentiation of ApoE4/4 monocytes. Arterioscler.
Thromb. Vasc. Biol. 1998, 18, 14241432.
[107] Tenger, C., Zhou, X., Apolipoprotein E modulates immune
activation by acting on the antigen-presenting cell. Immu-
nology 2003, 109, 392 397.
145
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
    • "Noteworthy, one characteristic of the aging process is the induction of low-grade chronic inflammation , often referred to as inflammaging, which is believed to be involved in the pathogenesis of several age-related chronic diseases, including AD and CVD [113]. An increasing number of evidence supports an APOE isoform-dependent modulation of the inflammatory response, with APOE4 appearing to be more associated with an overactive pro-inflammatory response to diverse stimuli (reviewed in [55] ). In a number of studies , APOE4 has been shown to be less effective in downregulating the activation of microglia and peripheral macrophages and suppressing the release of proinflammatory cytokines and other inflammatory mediators both in vitro and in vivo [114][115][116][117][118] . "
    [Show abstract] [Hide abstract] ABSTRACT: The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age-related diseases, including cardiovascular and Alzheimer’s disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype.
    Full-text · Article · Dec 2016
    • "Influence on vitamin E content in plasma, tissues and cells [69] 641 [82]. AD carrying E4 allele better counteract to the adverse effect of oxidative stress and chronic inflammation than do non-E4 carriers [83]. "
    [Show abstract] [Hide abstract] ABSTRACT: Aging is a complex biological phenomenon in which the deficiency of the nutritional state combined with the presence of chronic inflammation and oxidative stress contribute to the development of many age-related diseases. Under this profile, the free radicals produced by the oxidative stress lead to the damage of DNA, lipids, and proteins with subsequent altered cellular homeostasis and integrity, in particular in cells of the immune system. Supplementation with vitamin E can protect against the deteriorating effects of oxidative stress, progression of degenerative diseases, altered inflammatory/immune response, and aging. Such a protective role has been well documented in immune cells from old animals describing how the vitamin E works both at cytoplasmaic and nuclear levels with an influence on many genes related to the inflammatory/immune response. All these findings have supported a lot of clinical trials in old humans and in inflammatory age-related diseases, which, however, have given contradictory and inconsistent results and even indicated a dangerous role of vitamin E in being able to affect mortality. Various factors can contribute to all the discrepancies, especially the doses and the various isoforms of vitamin E family (α, β, γ, δ) tocopherols and the corresponding tocotrienols used in different trials. However, the more plausible gap is the poor consideration of the vitamin E–gene interactions that may open new roadmaps for a correct and personalized vitamin E supplementation in aging and age-related diseases with satisfactory results in order to reach healthy aging and longevity. This peculiar nutrigenomic and/or nutrigenetic aspect is herein reported and discussed in the light of specific polymorphisms affecting vitamin E bioactivity.
    Chapter · May 2016 · PLoS ONE
    • "Of the three common alleles of APOE, the so-called 'thrifty' ε4 allele is an ancestral allele that has been selected because it protects against some infectious diseases and increases cholesterol[38, 39]; thus, APOE ε4 may improve survival in populations experiencing food scarcity or poverty[38] . Jofre-Monseny et al. also reported that APOE ε4 plays a role in protecting against certain infectious diseases, and may have provided an initial evolutionary advantage related to pathogen resistance in developing countries[38] . Economic expansion, gradual adoption of a Western lifestyle (including a high-fat diet), low levels of physical activity, and long life expectancy have resulted in a shift from infectious diseases to non-communicable diseases. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Increasing age is associated with elevated risk of non-communicable diseases, including dementia and Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is a risk factor not only for AD, but also for cognitive decline, depressive symptoms, stroke, hypertension, coronary heart disease, cardiovascular disease, and diabetes. The Lao People's Democratic Republic (Laos) is undergoing development; consequently, life expectancy has risen. To evaluate the future risk of non-communicable diseases, we investigated APOE genotypes and anthropometric characteristics in the Laotian population. Methodology/principal findings: Subjects were 455 members of the Lao Loum majority and 354 members of ethnic minorities. APOE genotypes, anthropometric characteristics, blood pressure, and blood glucose were recorded. To compare individual changes, health examination data collected 5 years apart were obtained from a subset of Lao Loum subjects. APOE ε4 allele frequencies were higher among minorities (31.3%) than among Lao Loum (12.6%). In Lao Loum, but not in minorities, mean waist circumference and blood pressure increased significantly across age groups. Comparisons of health conditions between the beginning and end of the 5-year period revealed significant increases in obesity and blood glucose levels in Lao Loum. APOE ε4 carriers exhibited significant increases in resting heart rate in both ethnic groups. Conclusions/significance: A higher ε4 allele frequency was observed in Laotian minorities than in the Laotian majority. Furthermore, higher obesity, blood pressure and blood glucose were observed in the middle-aged ethnic majority. Therefore, given these genetic and non-communicable disease risk factors, it seems likely that as the Laotian population ages, elevated rates of non-communicable aging-related diseases, such as dementia, will also become more prevalent.
    Full-text · Article · May 2016
Show more