Biochimica et Biophysica Acta 1822 (2012) 657–663

Contents lists available at SciVerse ScienceDirect

Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbadis

Review

Antioxidants in Down syndrome☆

Ira T. Lott ⁎
Department of Pediatrics and Neurology, School of Medicine, University of California Irvine (UCI), Orange, CA 92868, USA

a r t i c l e i n f o a b s t r a c t

Article history: Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse
Received 31 October 2011 models of DS share some structural and functional abnormalities that parallel findings seen in the human
Received in revised form 13 December 2011 phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a plat-
Accepted 14 December 2011
form for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with
Available online 21 December 2011
oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated dur-
Keywords:
ing processes related to oxidative stress may have a direct role in producing the neuropathology of DS includ-
Antioxidant ing the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are
Oxidative stress considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been
Down syndrome described in DS and in AD in the general population. However, intervention trials using standard antioxidant
Alzheimer disease supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biolog-
Antioxidant clinical trial ical role of oxidative stress in DS and its relationship to abnormalities in both development and aging within
Mitochondrial disorder the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction publications were not excluded if considered relevant to the topics.

Oxidative stress is part of the fundamental biology of Down syn-
drome (DS). As the most common genetic cause of intellectual disabili-
ty, DS is due to trisomy of all or part of the chromosome 21. With few
exceptions, all of the genes of known function are located on the long
arm of chromosome 21. The gene sequence of chromosome 21 has
been carried out with 99.7% coverage [1]. Among the more than 500
genes on chromosome 21, functional information exists on about 150
genes. Of these, there are 18 that effect gene expression and over 20
that effect metabolic functioning [2]. Chromosome 21 contains several
genes that have been implicated in oxidative stress related to neurode-
generation including Cu/Zn superoxide dismutase (SOD1), amyloid
precursor protein (APP), Ets-2 transcription factors, Down Syndrome
Critical Region 1 (DSCR1) stress-inducible factor, beta-site APP cleaving
enzyme (BACE) and S100 [3–5]. In this chapter, investigations underly-
ing oxidative stress in DS will be discussed with an emphasis on those
which have led to therapeutic intervention trials. The scope of the review
included a search of PUBMED, MEDLINE AND APAPsychNET Direct
(1970–2011). The term “Down Syndrome” was used in combination
with the appropriate review target in the individual sections of this
report (i.e. mouse models, dementia, clinical trials, etc.). A principle
focus was on selected publications over the past 5 years, but older
☆ This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treat-
ment in Disease.
⁎ UC Irvine Medical Center, Department of Pediatrics ZC 4482, 101 The City Dr.,
Orange, CA 92868, USA. Tel.: + 1 714 456 5333; fax: + 1 714 456 8466.
E-mail address: itlott@uci.edu.
The reference list of articles identified by this search was selected for
relevance.
2. Mouse models of DS and oxidative stress
Mouse models have been used, in part, to determine how the
genes on human chromosome 21 lead to the tissue-wide abnormali-
ties seen in DS [6]. There is 80% synteny between human chromo-
some 21 (Hsa 21) and mouse chromosome 16 meaning that specific
genes are localized on the same chromosome in both the human
and mouse species. Approximately 175 genes are highly conserved
between Hsa 21 and the mouse genome although the correspondence
varies with the different models [7]. The mouse strains labeled
Ts65Dn, Ts1Yey, Ts1Cje, and Ts1Rh are trisomic for the segments of
mouse chromosome 16 that are homologous to Hsa 21. The relation-
ship of these models to one another and to genes on mouse chromo-
some 16 is shown in Fig. 1 [8]. The most commonly studied mouse
model is Ts65Dn which shares a number of structural and functional
neurological similarities with individuals who have DS. These include
abnormalities in basal forebrain cholinergic neurons and synapses,
reduction of cell density in the hippocampus of aged mice, reduced
dendritic branching in layer III pyramidal cells, and abnormalities
in the ability to induce long-term potentiation [9–12]. The Ts65Dn
mice also show spatial and non-spatial learning disabilities [13]. The
advantages of using mouse models for understanding various abnor-
malities in DS such as oxidative stress are numerous and include the
ability to study a sufficient number of animals in a short time, genetic
engineering for individual genes or chromosomal regions, control for

0925-4439/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbadis.2011.12.010
658 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
Mouse syntenic regions
MMU16
MMU17
MMU10
Fig. 1. Schematic representation of mouse models of trisomy 21. The first bar on the left
represents mouse chromosomal regions (MMU10, MMU16, and MMU17) that are syn-
tenic to human chromosome 21 (Hsa21). This bar is proportional to the number of
genes carried by the fragment. The approximate mapping of the genes is shown on
the left of the bar. All, except one, models are syntenic to MMU16. The estimated
number of syntenic genes is indicated on the right of each bar for each mouse model.
Reprinted from American Journal of Medical Genetics Part C (Seminars in Medical
Genetics), 154C, Roubertoux P and Carlier M, Mouse Models of Cognitive Disabilities
in Trisomy 21 (Down Syndrome), 400–416, 2010, with permission from John Wiley
and Sons.
genetic background, low cost of screening, ability to study both devel-
oping and mature subjects, modeling therapeutic interventions and
the lack of postmortem delays [6,14].
Oxidative stress represents an imbalance between the production
of reactive oxygen species (ROS) and the ability of a biological system
to detoxify the reactive intermediates or to repair the resulting
damage. Toxic effects may be caused through the production of lipid
peroxidation products and these compounds are increased in the
brains of two mouse models of DS called Ts1Cje and Ts2Cje [15].
The TsiCje model excludes APP and SOD1 yet shows evidence of oxi-
dative stress as characterized by decreased mitochondrial membrane
potential and other biomarkers [16]. In Ts65Dn mice, supplementa-
tion of the antioxidant α-tocopherol from the embryonic stage on-
ward showed improvement of spatial learning and alertness in the
treated mice but no amelioration of background hyperactivity [17].
There was also improvement in hypocellularity in the dentate gyrus
in the treated mice. In another study, markers of oxidative stress
were found to be elevated in Ts65Dn brain and treatment with α-
tocopherol was associated with improved performance on spatial
working memory tasks and an attenuation in cholinergic neuronal
pathology in forebrain [18]. A nootropic drug with antioxidant prop-
erties showed mixed results in cognition and behavior of Ts65Dn
mice [19]. Thus, several treatment approaches to oxidative stress
have shown some benefit in mouse models of DS.
3. Biological foundation of oxidative stress in individuals with DS
It is the area of Alzheimer disease (AD) that oxidative stress in DS
seems to have the most significance. By 40 years of age, virtually
all individuals with DS show the characteristic neuropathological
changes of AD including beta-amyloid (Aβ) plaques and neurofibril-
lary tangles [20]. The accumulation of Aβ plaques in brain is seen
across the lifespan in DS with appearance by 8 years of age or before
[21]. In most individuals with DS, the rate of Aβ deposition increases
markedly between 35 and 45 years and becomes associated with
neurofibrillary tangles [22].
The lack of balance in the metabolism of ROS appears to have a di-
rect role in producing the neuropathology of DS [23–25]. Oxidative
damage has been observed in brain tissue from individuals with DS
[26,27]. In the brain of fetuses with DS, two forms of glycation end
products indicative of cellular oxidative stress were increased [28].
Cortical neurons from fetuses with DS show intracellular accumula-
tion of ROS that lead to neuronal apoptosis [29]. These findings sug-
gest that glycoxidation occurs very early in the life of individuals
with DS. Early deposition of oxidized Aβ has also been seen within
plaques from a 31 year old individual with DS, a finding which sug-
gests that oxidative modification of Aβ may be an early event in the
pathogenesis of AD [30]. Oxidative stress is also manifested in the
brain of patients with AD in the general population [31,32]. Cultured
human cortical neurons have provided a model in which oxidative
stress may be treated in DS. Peptides released from naturally occur-
ring glial proteins have been shown to possess potent antioxidative
effects in cultured DS cortical neurons [33].
4. Genes encoded on chromosome 21 and their relationship to
oxidative stress
SOD1 has been shown to be a part of many physiological processes
such as transcription regulation, protein activation, bioenergy output,
and cell proliferation. Simultaneous disorders of SOD1 and the uncou-
pling of proteins related to mitochondrial dysfunction have been im-
plicated in the pathogenesis of AD and may precede Aβ deposition
[34,35]. SOD1 gene is located just above the DS minimal critical region
and more than 99% are trisomic for this gene [36]. The Down syn-
drome critical region is located on the long arm (q) of chromosome
21 and is considered to be responsible for some, if not all, of the fea-
tures of the DS phenotype.
This cytosolic enzyme catalyzes the dismutation of superoxide
radicals that are formed during oxidative metabolism to hydrogen
peroxide and oxygen. Under normal circumstances, the hydrogen
peroxide is removed by glutathione peroxidase or catalase. However,
brain levels of both of these enzymes maybe low in mammalian
species causing an imbalance between the first and second step in
superoxide catabolism which then results in an increase in hydroxyl
radicals [37]. Hydroxyl radicals are highly reactive compounds that
can damage neuronal membranes, cellular structures and organelles
[38]. In DS, the exact role played by SOD1 overexpression is not
clear. For example, congenital heart disease which is seen in up to
50% of children with DS does not appear to be associated with abnor-
malities in redox metabolism [39]. However, circulating endothelial
progenitor cells involved in angiogenesis in DS have an increased sus-
ceptibility to oxidative stress which is thought to be related to the
immune disorder associated with this syndrome [40]. Proliferation
defects and gene expression dysregulation seen in neural progenitor
cells in a mouse model of DS (Ts1Cje) required neither overexpres-
sion of SOD1 or APP [41]. In double APP/SOD1 transgenic mice, SOD1
overexpression prevented toxicity from APP and significantly in-
creased the lifespan of the animals [42]. The relationship of genes
encoded on chromosome 21 to oxidative stress has been previously
reviewed [25].
Ets-2 is a protein that is encoded by Ets-2 gene and functions as a
transcription factor that is overexpressed on chromosome 21. Ets-2
has been involved in multiple cellular processes including differenti-
ation, maturation and signaling cascades [43,44]. It appears to be
markedly upregulated by oxidative stress. In fetal cortical cells Ets-2
induces a stereotyped pattern of apoptotic changes leading to neuro-
nal cell death [4]. In AD, increased expression of Ets-2 is associated
with pathological markers suggesting that oxidative stress-driven
Ets-2 upregulation contributes to neuronal death in both DS and AD.
In Ts65Dn mouse, the Ets-2 tumor repressor gene has been related
to a reduced incidence of solid tumors, one of the multiple complex
genetic mechanisms that underlie cancer pathogenesis in DS [45,46].
 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
APP is involved in the development of AD and DS [47,48]. Aβ plasma
levels are increased in DS and soluble forms of Aβ have been seen down
to 21 weeks of gestational age [49,50]. Oxidized Aβ is seen in a high per-
centage of diffuse and core plaques within the brains of individuals with
DS and oxidative modification of Aβ may be an early event in plaque
biogenesis. Animal exposure studies to Aβ demonstrate that the neuro-
biological factors that foster AD may have their origins in early life and
result from interplay between the environment, epigenetic factors and
oxidative stress [51]. Environmental influences occurring during brain
development inhibit DNA methyltransferases, thus hypomethylating
promoters of genes associated with AD such as APP. This early life im-
printing may act later in life to increase the levels of APP and Aβ. In-
creased Aβ levels may promote the production of ROS, damage DNA,
and accelerate neurodegenerative events. However, the resulting pic-
ture is complex since other AD-associated genes may be repressed rath-
er than overexpressed. Thus, hypo- or hypermethylation of AD-specific
genes and their subsequent effect on Aβ production may be one of the
factors accounting for the variability of the incidence of AD-type
dementia in individuals with DS.
DSCR1 is a stress-inducible factor located on chromosome 21 that
is modulated by oxidative stress [52]. DSCRI is also known as Adapt78
and RCAN (regulator of calcineurin). Transient overexpression of
DSCR1 appears to be protective but chronic upregulation is deleteri-
ous to cells likely through the expression of SOD1 [53]. DSCR1 is also
upregulated in AD [54]. DSCR1 has been found to be a regulator
of the calcineurin signaling pathway related to the reduced risk of
certain cancers in individuals with DS [55].
DYRK1A is a gene that is overexpressed in individuals with trisomy
21 as well as mouse models for DS. This gene may be responsible for
processes affecting synaptic plasticity and memory consolidation. Over-
epxression of DYRK1A in the brain of individuals with DS causes neuro-
fibrillary degeneration via hyperphosphorylation of tau [56]. In aged
mice overexpressing DYRK1A, marked motor abnormalities were asso-
ciated with cell loss in the CA1–CA3 areas of the hippocampus and in
the dentate gyrus [57]. Epigallocatechin gallate — a member of a natural
polyphenols family, is found in great amount in green tea leaves. It ap-
pears to be a specific and safe DYRK1A inhibitor which rescues the brain
defects in transgenic mouse that overexpresses the gene [58]. The rela-
tionship of this effect to oxidative stress has not been elucidated.
In summary, overexpression of several chromosome 21 genes
leads to a genetic imbalance that creates a “vicious cycle” by which
oxidative stress is exacerbated resulting in further genetic imbalance.
By virtue of their role in oxidative metabolism, mitochondria may
serve as one of the pathways for this genetic imbalance.
Fig. 2. mtDNA Regulatory Control Region (RCR) mutation frequency in the peripheral tissue samples from control and dementia patients. (A) Analysis of mtDNA RCR mutation
frequency in the frontal cortex and serum DNA (CF-DNA) from the same AD and control cases (n = 6, between the ages of 81 to 95 years). (B) Analysis of lymphoblastoid
cell lines (LCLs) from DS, DS and AD, AD, and controls (n = 5–7, between the ages of 45 to 62 years). Reprinted from Journal of Alzheimer’s Disease, 20, Coskun P, Wyrembaka
J, Derbereva O, Melkonian G, Doran E, Lott IT, Head E, Cotman CW, and Wallace D, Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer’s Disease and Down Syndrome
Dementia, S293-S310, 2010, with permission from IOS press.
659
5. Mitochondria and oxidative stress in DS
Mitochondria are subcellular organelles that contain enzymes for
ATP production, calcium homeostasis, ROS, and apoptotic signaling
[59]. As such, they are a target for oxidative stress. Dysfunction of
mitochondria has surfaced as one of the most discussed hypotheses
for a trigger in AD.
Within the general population and to some extent in DS, the
strongest genetic association with dementia is the ε-4 allele of the
apolipoprotein gene (Apoε4) [60,61]. Cleavage of Apoε4 yields pep-
tides that increase oxidative stress within the mitochondria [62].
Mitochondrial dysfunction has been observed in individuals with
AD as manifested by defects in oxidative phosphorylation specifically
in the respiratory complex IV [63,64]. The Aβ peptide itself can
elevate oxidative stress by entering the mitochondria and producing
ROS [65,66]. Mitochondrial dysfunction is one of the earliest events
in the brains of mutant mice overexpressing APP as well as tau and
presenilin1 [65,67].
Somatic mitochondrial DNA mutations may be elevated 15-fold in
AD brain [68]. In DS, mitochondrial dysfunction and elevated levels of
oxidative stress have been reported in neuronal cell cultures, brain,
fibroblasts, erythrocytes and urine [69]. While somatic mitochondrial
DNA control region mutations accumulate with age in post-mitotic
tissues including the brain, the level of these mutations is markedly
elevated in the brains of individuals with DS and AD in the general
population [70]. This increased mutation rate is also seen in peripher-
al blood and in lymphoblastoid cell lines (Fig. 2). Mitochondrial dys-
function in DS is not only seen in the aging-AD process but earlier
in life as well. In human neural progenitor cells from fetal cortex,
those genes overexpressed on chromosome 21 (such as S100B) dis-
turb the redox state within mitochondria and ultimately impair neu-
rogenesis [71]. Human skin fibroblasts from fetuses with DS show
that a complex I deficit may be responsible for the oxidative defect
in mitochondria [72]. The mitochondria from DS fibroblasts are par-
ticularly sensitive to okadaic acid, a toxin that may induce malforma-
tions and interfere with the growth of cell lines [73]. In another study
evaluating the cause of mitochondrial dysfunction in DS, impairment
of the methyl cycle was shown to effect mitochondrial methyl
availability and glutathione concentrations [74]. Mitochondrial ab-
normalities in mouse models for DS have been discussed in the intro-
ductory section to these models.
Taken collectively, the findings of mitochondrial DNA mutations
in DS and AD may be responsible for dementia in this disorder. Mito-
chondrial dysfunction also occurs at early age epochs in DS and could
660 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
provide a platform for early effects of oxidative stress. Measures of
mitochondrial overproliferation and deletion have been proposed
as a marker for AD [75]. Mitochondrial deficits have been noted in
non-neural peripheral tissues and there are a number of studies
that have tried to capture peripheral effects of oxidative stress.
6. Biomarkers of oxidative stress in individuals with DS
In a study aimed at defining the relationship between peripheral
markers of oxidative stress and cognitive ability in adults with DS,
low ratios of SOD1 to glutathione peroxidase were associated with
worse memory ability, a finding which held after adjustment for
gender, age, and the use of nutritional supplements. However, there
was no relationship of the above findings to measures of F-
isoprostanes, a proxy for lipid peroxidation [76]. The authors con-
cluded that relationship between antioxidant capacity and cognitive
phenotype in DS is complex and could be affected by the interaction
of several genes rather than a formulation of a simple association.
Individuals with DS often have high uric acid concentration, a me-
tabolite that may have antioxidant properties. For example, children
with DS had higher level of uric acid and total antioxidant capacity
than the control group whereas no differences were found in adults
[77]. However, in another study of children with DS, increased uric
acid concentrations were associated with an increase in oxidative stress
markers as measured by elevated allantoin concentrations in compari-
son to controls [78]. The mediator of this increase in reactive oxygen
species may be xanthine oxidase. Allantoin and F-isoprostanes appear
to be related to the oxidative assault that may occur as the result of
chemotherapy in women with breast cancer in the general population
[79]. The role of uric acid and oxidative stress in DS will require elucida-
tion from additional studies.
The antioxidant properties of melatonin as well as the neurotoxic
factors measured by biomarkers in the kynurenine pathway were
studied in a small group of children with DS [80]. Plasma melatonin
and urinary kynurenine concentrations were lower than in age-
matched controls but levels of kynurenic and anthranilic acids were
elevated. The authors concluded that this pattern of biomarkers con-
stituted an added oxidative risk to children with DS.
Markers of homocysteine and folic acid were examined in 42 preg-
nant mothers with a previous history of having delivered a child
with DS in comparison to 48 control pregnant women. The pattern
of metabolites suggested to the authors that mothers who delivered
a child with DS had an abnormal oxidant/antioxidant ratio [81].
Gelsolin is actin-binding protein that binds to Aβ and inhibits
fibrillogenesis, a pathogenetic step in AD. The active metabolite of
gelsolin is a proteolytic product which contains a carboxy-terminal
fragment (CTF). Gelsolin-CTF is decreased in the frontal cortex of
adults with DS (43–63 years) but not in younger individuals (0.5–
23 years). There was a correlation in brain between the gelsolin frag-
ment and both soluble and total concentrations of Aβ40 and Aβ42.
This suggests a potential role for gelsolin in increasing of Aβ levels
in DS brain. Oxidative pathways may be involved since gelsolin is
cleaved under apoptotic conditions involving oxidative stress [82].
Nitric oxide is a regulatory molecule that may play a role in the
pathogenesis of AD [83]. Inflammation appears to be a mediator of
nitric oxide effect through glial cells that produce pro-inflammatory
and neurotoxic factors [84]. Neopterin is an indicator for systemic in-
flammation as well as immune activation. This compound increases
with age in DS and appears related to the development of dementia
[85]. In a large population of individuals with DS (401), there was a
strong correlation between neopterin levels in plasma and the pro-
duction of nitric oxide [86]. These findings are similar to those
found in the plasma of AD patients in the general population [87].
Neopterin measures may reflect oxidative stress in DS and dementia.
Biomarkers of oxidative and inflammatory stress in blood and
urine have the advantage of easy accessibility but their ability to
predict oxidative changes in the brain has not yet been established
conclusively. Peripheral markers carry a promise to assist in the
evaluation of oxidative risk throughout the lifespan with potential in-
tervention through antioxidant trials. In evaluating the reliability
of peripheral markers, of particular importance is the validation of
assays, determination of the steady state concentrations of the bio-
markers, utilization of multianalyte panels, and correlation with in
vivo imaging findings [88]. The relationship of peripheral marker to
cerebrospinal fluid (CSF) concentrations has been rarely studied, a
point for consideration in future studies since CSF markers may
more closely reflect brain function than plasma. However, even with
CSF markers, lower levels of cytokines may reflect influx from plasma
rather than intrathecal synthesis [89].
7. Antioxidant trials in the general AD population
In the general population, studies assessing whether the consump-
tion of antioxidants from both dietary and supplemental sources in
preventing AD have shown mixed results [90]. In the Chicago Health
and Aging Project, increased vitamin E intake from dietary sources re-
duced the risk for dementia in individuals who were positive for
Apoε4 allele. However, actual supplements of vitamin E were not
associated with benefits. Vitamin E administration did not influence
the conversion of mild cognitive impairment to dementia [91]. Dietary
intake of beta-carotene or vitamin C did not influence the course of
dementia. [92]. In the Rotterdam study, no effect of the ApoE genotype
was found but high vitamin C and vitamin E intake was associated with
reduced risk for AD [93]. No association between disease risk and intake
of beta-carotene, vitamin E, and vitamin C was found in the Washington
Heights-Inwood Columbia Aging Project, the Honolulu-Aging Study,
and the Cache County Study [94–96]. In another study, supplements
of vitamins C and E together reduced the risk for AD [97].
8. The canine model for the study and treatment of oxidative
stress
The often contradictory results in human trials have been one of
the factors leading to the investigation of a canine animal model of
aging which has had implications for antioxidant trials in DS. Beagle
dogs have a median lifespan of 13.5 years and show many of the
changes of AD including evidence of oxidative stress [98]. Fig. 3
shows the relationship of oxidized Aβ in the brains of individuals
with DS, AD as compared to the canine model. Their neuropathology
parallels many of the changes of AD including cortical atrophy, neuro-
nal loss, Aβ plaques, and amyloid angiopathy and oxidative damage.
With aging, this particular breed of beagle dog exhibits decline in
executive functioning, learning, and memory. However, the model is
somewhat incomplete as the dogs do not develop neurofibrillary
changes. Nonetheless, many of the neuropathological features in the
canines correlate with the extent of cognitive decline. Topographic
concentrations of Aβ in the dogs exhibit patterns that parallel those
in human brain [99]. The cloning, sequencing and expression of APP
isoforms and the enzymes related to their processing also parallel
the findings in human brain [100]. The dogs also show cholinergic
hypofunction similar to that seen in human AD brain, suggesting
that this model could be used for therapeutic screening as well as un-
derstanding the links between cholinergic functioning, Aβ pathology,
and cognitive decline [101].
Of particular interest to potential clinical trials in DS was an anti-
oxidant supplementation study in which cellular and mitochondrial
antioxidants were given to the beagle dogs [102]. A broad based
diet in the treated group of dogs contained dl-alpha-tocopherol ace-
tate, l-carnitine, dl-alpha-lipoic acid, ascorbic acid and other dietary
antioxidants. After one and six months of treatment, the animals
were tested for spatial attention ability [103,104]. The treated aged
animals performed much better than controls and better than the
 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
A B
Fig. 3. Characterization of plaques containing oxidized Aβ in the brain tissues. Diffuse plaques in the prefrontal cortex contain oxidized Aβ in the brain of: (A) an aged non-
demented 86 year old individual; (B) a 31 year old non-demented individual with DS; and (C) an aged canine. Scale = 50 μm.
younger animals. The beneficial effects of the antioxidant diet were
enhanced further by environmental stimulation.
9. Antioxidant trials in DS
Since individuals with DS share many of the patterns of oxidative
stress seen in the canine model, a parallel clinical trial was of interest.
We carried out a randomized, double-blind, placebo-controlled trial
to assess whether daily antioxidant supplementation (900 IU of α-
tocopherol, 200 mg of ascorbic acid and 600 mg of alpha-lipoic acid)
was effective, safe, and tolerable for 53 individuals with DS and AD-
type dementia [105]. The outcome measures comprised a battery of
neuropsychological assessments administered at baseline and every
6 months throughout two years of study. Compared to the placebo
group, those individuals receiving the antioxidant supplement showed
neither an improvement in cognitive functioning nor a stabilization
of cognitive decline. Mean plasma levels of α-tocopherol increased
~2-fold in the treatment group and were consistently higher than the
placebo group over the treatment period. Pill counts indicated good
compliance with the regimen. No serious adverse events attributed to
the treatment were noted. We conclude that antioxidant supplementa-
tion is safe, though ineffective as a treatment for dementia in individuals
with DS and AD-type dementia.
A similar lack of antioxidant efficacy was noted in a study of 156
infants with DS b7 months of age. Supplementation of the diet with
antioxidants, and folinic acid did not show efficacy in a randomized
controlled trial [106].
Another approach to treating oxidative stress in AD has been
through environmental modification, particularly exercise. There is ev-
idence from experimental models that exercise has time-dependant
benefits to learning and memory [107]. While definitive clinical
studies are lacking, there is evidence among older people with AD
in the general population that weight-bearing exercise reduces the
decline in activities of daily living [108]. Neurogenesis appears to
be enhanced by environmental factors such as exercise, environ-
mental enrichment and dietary energy restriction [109]. In this con-
text, exercise was tested in a small study of adults with DS and lipid
peroxidation, a marker of oxidative stress, was reported to be re-
duced in saliva [110]. Plasma oxidative stress markers were reduced
in adolescents with DS who underwent a 12 week aerobic training
program [111]. The role of exercise in lowering oxidative stress in
DS merits further investigation.
Many individuals with DS receive complementary and alternative
therapies, some of which are aimed at oxidative stress. The pros and
cons of pharmaceutical, nutritional, botanical and stimulatory thera-
pies for AD have been reviewed [112]. The author concludes that
potential risks of both approved and non-approved therapies should
661
C
be weighed against potential risk and disease progression. Targets
that attempt to treat several dysfunctions simultaneously may hold
promise for future studies of alternative therapies.
10. Conclusions
Oxidative stress is strongly associated with both development
and aging in DS. The mouse models of DS that provide homology to
chromosome 21 have afforded a fruitful approach for the experimen-
tal manipulation of oxidative stress through strategic interventions.
Several genes on chromosome 21 have been associated with
oxidative stress and their overexpression may contribute to a genetic
imbalance in DS which propagates the development of ROS. Mito-
chondrial dysfunction is impacted by and also creates oxidative stress
in DS. Mitochondria may be a common pathway by which oxidative
stress affects basic mechanisms underlying DS and AD.
However, despite strong animal evidence for oxidative stress and its
amelioration, clinical trials in both DS and AD have been disappointing
to date. Intervention, once dementia has begun in DS, is unlikely to be
therapeutic, in part because of the underlying intellectual disability
and factors related to decreased synpatogenesis in the disorder. Prophy-
lactic trials may hold more encouragement in DS and it is possible
that early intervention with strategically developed antioxidants
may positively impact intellectual functioning decades before de-
mentia sets in. But which antioxidants? The generation of newer
classes of antioxidants and new approaches to intervention will be
needed to combat oxidative stress in both AD and DS.
Acknowledgements
This research was supported by NIH grants AG-21912, HD-65160,
AG-16573 Alzheimer's Disease Research Center. Nina Movsesyan,
PhD, assisted in the preparation of this manuscript.
References
[1] M. Hattori, A. Fujiyama, T.D. Taylor, H. Watanabe, T. Yada, H.S. Park, A. Toyoda, K.
Ishii, Y. Totoki, D.K. Choi, Y. Groner, E. Soeda, M. Ohki, T. Takagi, Y. Sakaki, S.
Taudien, K. Blechschmidt, A. Polley, U. Menzel, J. Delabar, K. Kumpf, R. Lehmann,
D. Patterson, K. Reichwald, A. Rump, M. Schillhabel, A. Schudy, W. Zimmermann,
A. Rosenthal, J. Kudoh, K. Schibuya, K. Kawasaki, S. Asakawa, A. Shintani, T.
Sasaki, K. Nagamine, S. Mitsuyama, S.E. Antonarakis, S. Minoshima, N. Shimizu,
G. Nordsiek, K. Hornischer, P. Brant, M. Scharfe, O. Schon, A. Desario, J. Reichelt,
G. Kauer, H. Blocker, J. Ramser, A. Beck, S. Klages, S. Hennig, L. Riesselmann, E.
Dagand, T. Haaf, S. Wehrmeyer, K. Borzym, K. Gardiner, D. Nizetic, F. Francis,
H. Lehrach, R. Reinhardt, M.L. Yaspo, The DNA sequence of human chromosome
21, Nature 405 (2000) 311–319.
[2] X. Sturgeon, K.J. Gardiner, Transcript catalogs of human chromosome 21 and
orthologous chimpanzee and mouse regions, Mamm. Genome, 22, 2011,
pp. 261–271.
662 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
[3] S.E. Antonarakis, R. Lyle, E.T. Dermitzakis, A. Reymond, S. Deutsch, Chromosome
21 and down syndrome: from genomics to pathophysiology, nature reviews,
Genetics 5 (2004) 725–738.
[4] P. Helguera, A. Pelsman, G. Pigino, E. Wolvetang, E. Head, J. Busciglio, ets-2 pro-
motes the activation of a mitochondrial death pathway in Down's syndrome
neurons, J. Neurosci. 25 (2005) 2295–2303.
[5] K.T. Chang, K.T. Min, Drosophila melanogaster homolog of Down syndrome
critical region 1 is critical for mitochondrial function, Nat. Neurosci. 8 (2005)
1577–1585.
[6] A. Salehi, M. Faizi, P.V. Belichenko, W.C. Mobley, Using mouse models to explore
genotype–phenotype relationship in Down syndrome, Ment. Retard. Dev. Disabil.
Res. Rev. 13 (2007) 207–214.
[7] I. Das, R.H. Reeves, The use of mouse models to understand and improve cogni-
tive deficits in Down syndrome, Dis. Models Mech. 4 (2011) 596–606.
[8] P.L. Roubertoux, M. Carlier, Mouse models of cognitive disabilities in trisomy 21
(Down syndrome), American journal of medical genetics, part C, Semin. Med.
Genet. 154C (2010) 400–416.
[9] A. Salehi, J.D. Delcroix, W.C. Mobley, Traffic at the intersection of neurotrophic
factor signaling and neurodegeneration, Trends Neurosci. 26 (2003) 73–80.
[10] A.M. Kleschevnikov, P.V. Belichenko, A.J. Villar, C.J. Epstein, R.C. Malenka, W.C.
Mobley, Hippocampal long-term potentiation suppressed by increased inhibi-
tion in the Ts65Dn mouse, a genetic model of Down syndrome, J. Neurosci. 24
(2004) 8153–8160.
[11] M.A. Kurt, M.I. Kafa, M. Dierssen, D.C. Davies, Deficits of neuronal density in CA1
and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of
Down syndrome, Brain Res. 1022 (2004) 101–109.
[12] A.C. Costa, M.J. Grybko, Deficits in hippocampal CA1 LTP induced by TBS but not
HFS in the Ts65Dn mouse: a model of Down syndrome, Neurosci. Lett. 382
(2005) 317–322.
[13] L.A. Hyde, D.F. Frisone, L.S. Crnic, Ts65Dn mice, a model for Down syndrome, have
deficits in context discrimination learning suggesting impaired hippocampal func-
tion, Behav. Brain Res. 118 (2001) 53–60.
[14] D. Patterson, Molecular genetic analysis of Down syndrome, Hum. Genet. 126
(2009) 195–214.
[15] K. Ishihara, K. Amano, E. Takaki, A.S. Ebrahim, A. Shimohata, N. Shibazaki, I. Inoue, M.
Takaki, Y. Ueda, H. Sago, C.J. Epstein, K. Yamakawa, Increased lipid peroxidation in
Down's syndrome mouse models, J. Neurochem. 110 (2009) 1965–1976.
[16] E.A. Shukkur, A. Shimohata, T. Akagi, W. Yu, M. Yamaguchi, M. Murayama, D.
Chui, T. Takeuchi, K. Amano, K.H. Subramhanya, T. Hashikawa, H. Sago, C.J.
Epstein, A. Takashima, K. Yamakawa, Mitochondrial dysfunction and tau hyper-
phosphorylation in Ts1Cje, a mouse model for Down syndrome, Hum. Mol.
Genet. 15 (2006) 2752–2762.
[17] M. Shichiri, Y. Yoshida, N. Ishida, Y. Hagihara, H. Iwahashi, H. Tamai, E. Niki,
alpha-Tocopherol suppresses lipid peroxidation and behavioral and cognitive
impairments in the Ts65Dn mouse model of Down syndrome, Free Radic. Biol.
Med. 50 (2011) 1801–1811.
[18] J. Lockrow, A. Prakasam, P. Huang, H. Bimonte-Nelson, K. Sambamurti, A.C.
Granholm, Cholinergic degeneration and memory loss delayed by vitamin E in
a Down syndrome mouse model, Exp. Neurol. 216 (2009) 278–289.
[19] N. Rueda, J. Florez, C. Martinez-Cue, Effects of chronic administration of SGS-111
during adulthood and during the pre- and post-natal periods on the cognitive
deficits of Ts65Dn mice, a model of Down syndrome, Behav. Brain Res. 188
(2008) 355–367.
[20] D.M. Mann, M.M. Esiri, The pattern of acquisition of plaques and tangles in the
brains of patients under 50 years of age with Down's syndrome, J. Neurol. Sci.
89 (1989) 169–179.
[21] I.T. Lott, E. Head, Alzheimer disease and Down syndrome: factors in pathogenesis,
Neurobiol. Aging 26 (2005) 383–389.
[22] K.E. Wisniewski, H.M. Wisniewski, G.Y. Wen, Occurrence of neuropathological
changes and dementia of Alzheimer's disease in Down's syndrome, Ann. Neurol.
17 (1985) 278–282.
[23] J. Kedziora, G. Bartosz, Down's syndrome: a pathology involving the lack of
balance of reactive oxygen species, Free Radic. Biol. Med. 4 (1988) 317–330.
[24] J. Busciglio, J.K. Andersen, H.M. Schipper, G.M. Gilad, R. McCarty, F. Marzatico, O.
Toussaint, Stress, aging, and neurodegenerative disorders, molecular mecha-
nisms, Ann. N. Y. Acad. Sci. 851 (1998) 429–443.
[25] I.T. Lott, E. Head, E. Doran, J. Busciglio, Beta-amyloid, oxidative stress and down
syndrome, Curr. Alzheimer Res 3 (2006) 521–528.
[26] G.P. Reynolds, A.J. Cutts, Free radical damage in Down's syndrome brain, Bio-
chem. Soc. Trans. 21 (1993) 221S.
[27] B.W. Brooksbank, M. Martinez, R. Balazs, Altered composition of polyunsaturated
fatty acyl groups in phosphoglycerides of Down's syndrome fetal brain, J. Neuro-
chem. 44 (1985) 869–874.
[28] P. Odetti, G. Angelini, D. Dapino, D. Zaccheo, S. Garibaldi, F. Dagna-Bricarelli, G.
Piombo, G. Perry, M. Smith, N. Traverso, M. Tabaton, Early glycoxidation damage
in brains from Down's syndrome, Biochem. Biophys. Res. Commun. 243 (1998)
849–851.
[29] J. Busciglio, B.A. Yankner, Apoptosis and increased generation of reactive oxygen
species in Down's syndrome neurons in vitro, Nature 378 (1995) 776–779.
[30] E. Head, W. Garzon-Rodriguez, J.K. Johnson, I.T. Lott, C.W. Cotman, C. Glabe,
Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syn-
drome, Neurobiol. Dis. 8 (2001) 792–806.
[31] P. Mecocci, U. MacGarvey, M.F. Beal, Oxidative damage to mitochondrial DNA is
increased in Alzheimer's disease, Ann. Neurol. 36 (1994) 747–751.
[32] M.A. Smith, G. Perry, P.L. Richey, L.M. Sayre, V.E. Anderson, M.F. Beal, N. Kowall,
Oxidative damage in Alzheimer's, Nature 382 (1996) 120–121.
[33] J. Busciglio, A. Pelsman, P. Helguera, O. Ashur-Fabian, A. Pinhasov, D.E. Brenneman,
I. Gozes, NAP and ADNF-9 protect normal and Down's syndrome cortical neurons
from oxidative damage and apoptosis, Curr. Pharm. Des. 13 (2007) 1091–1098.
[34] Z. Wu, Y. Zhao, B. Zhao, Superoxide anion, uncoupling proteins and Alzheimer's
disease, J. Clin. Biochem. Nutr. 46 (2010) 187–194.
[35] K.J. Young, J.P. Bennett, The mitochondrial secret(ase) of Alzheimer's disease,
J. Alzheimer's Dis. 20 (Suppl 2) (2010) S381–S400.
[36] J.R. Korenberg, H. Kawashima, S.M. Pulst, T. Ikeuchi, N. Ogasawara, K. Yamamoto,
S.A. Schonberg, R. West, L. Allen, E. Magenis, et al., Molecular definition of a
region of chromosome 21 that causes features of the Down syndrome pheno-
type, Am. J. Hum. Genet. 47 (1990) 236–246.
[37] S. Szymonik-Lesiuk, G. Czechowska, M. Stryjecka-Zimmer, M. Slomka, A. Madro,
K. Celinski, M. Wielosz, Catalase, superoxide dismutase, and glutathione perox-
idase activities in various rat tissues after carbon tetrachloride intoxication,
J. Hepato-Biliary-Pancreatic Surg. 10 (2003) 309–315.
[38] J.A. Badwey, M.L. Karnovsky, Active oxygen species and the functions of phago-
cytic leukocytes, Annu. Rev. Biochem. 49 (1980) 695–726.
[39] O. Akinci, E. Mihci, S. Tacoy, F. Kardelen, I. Keser, M. Aslan, Neutrophil oxidative
metabolism in Down syndrome patients with congenital heart defects, Environ.
Mol. Mutagen. 51 (2010) 57–63.
[40] V. Costa, L. Sommese, A. Casamassimi, R. Colicchio, C. Angelini, V. Marchesano, L.
Milone, B. Farzati, A. Giovane, C. Fiorito, M. Rienzo, M. Picardi, B. Avallone, M.
Marco Corsi, B. Sarubbi, R. Calabro, P. Salvatore, A. Ciccodicola, C. Napoli, Impair-
ment of circulating endothelial progenitors in Down syndrome, BMC Med.
Genomics 3 (2010) 40.
[41] R.X. Moldrich, L. Dauphinot, J. Laffaire, T. Vitalis, Y. Herault, P.M. Beart, J. Rossier,
D. Vivien, C. Gehrig, S.E. Antonarakis, R. Lyle, M.C. Potier, Proliferation deficits
and gene expression dysregulation in Down's syndrome (Ts1Cje) neural pro-
genitor cells cultured from neurospheres, J. Neurosci. Res. 87 (2009) 3143–3152.
[42] J. Borg, E. Chereul, Differential MRI patterns of brain atrophy in double or sin-
gle transgenic mice for APP and/or SOD, J. Neurosci. Res. 86 (2008)
3275–3284.
[43] K. Macleod, D. Leprince, D. Stehelin, The ets gene family, Trends Biochem. Sci. 17
(1992) 251–256.
[44] B. Wasylyk, S.L. Hahn, A. Giovane, The Ets family of transcription factors, Eur.
J. Biochem. 211 (1993) 7–18 FEBS.
[45] A. Yang, R.H. Reeves, Increased survival following tumorigenesis in Ts65Dn mice
that model Down syndrome, Cancer Res. 71 (2011) 3573–3581.
[46] L.E. Reynolds, A.R. Watson, M. Baker, T.A. Jones, G. D'Amico, S.D. Robinson, C.
Joffre, S. Garrido-Urbani, J.C. Rodriguez-Manzaneque, E. Martino-Echarri, M.
Aurrand-Lions, D. Sheer, F. Dagna-Bricarelli, D. Nizetic, C.J. McCabe, A.S. Turnell,
S. Kermorgant, B.A. Imhof, R. Adams, E.M. Fisher, V.L. Tybulewicz, I.R. Hart, K.M.
Hodivala-Dilke, Tumour angiogenesis is reduced in the Tc1 mouse model of
Down's syndrome, Nature 465 (2010) 813–817.
[47] A. Rovelet-Lecrux, D. Hannequin, G. Raux, N. Le Meur, A. Laquerriere, A. Vital, C.
Dumanchin, S. Feuillette, A. Brice, M. Vercelletto, F. Dubas, T. Frebourg, D. Campion,
APP locus duplication causes autosomal dominant early-onset Alzheimer disease
with cerebral amyloid angiopathy, Nat. Genet. 38 (2006) 24–26.
[48] V.P. Prasher, M.J. Farrer, A.M. Kessling, E.M. Fisher, R.J. West, P.C. Barber, A.C.
Butler, Molecular mapping of Alzheimer-type dementia in Down's syndrome,
Ann. Neurol. 43 (1998) 380–383.
[49] N. Schupf, B. Patel, W. Silverman, W.B. Zigman, N. Zhong, B. Tycko, P.D. Mehta, R.
Mayeux, Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in
adults with Down syndrome, Neurosci. Lett. 301 (2001) 199–203.
[50] J.K. Teller, C. Russo, L.M. DeBusk, G. Angelini, D. Zaccheo, F. Dagna-Bricarelli, P.
Scartezzini, S. Bertolini, D.M. Mann, M. Tabaton, P. Gambetti, Presence of soluble
amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome,
Nature Med. 2 (1996) 93–95.
[51] N.H. Zawia, D.K. Lahiri, F. Cardozo-Pelaez, Epigenetics, oxidative stress, and
Alzheimer disease, Free Radic. Biol. Med. 46 (2009) 1241–1249.
[52] D.R. Crawford, K.P. Leahy, N. Abramova, L. Lan, Y. Wang, K.J. Davies, Hamster
adapt78 mRNA is a Down syndrome critical region homologue that is inducible
by oxidative stress, Arch. Biochem. Biophys. 342 (1997) 6–12.
[53] G. Ermak, C. Cheadle, K.G. Becker, C.D. Harris, K.J. Davies, DSCR1(Adapt78)
modulates expression of SOD1, FASEB J. 18 (2004) 62–69.
[54] C.D. Harris, G. Ermak, K.J. Davies, Multiple roles of the DSCR1 (Adapt78 or
RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease, cellu-
lar and molecular life sciences, CMLS 62 (2005) 2477–2486.
[55] K.H. Baek, A. Zaslavsky, R.C. Lynch, C. Britt, Y. Okada, R.J. Siarey, M.W. Lensch, I.H.
Park, S.S. Yoon, T. Minami, J.R. Korenberg, J. Folkman, G.Q. Daley, W.C. Aird, Z.
Galdzicki, S. Ryeom, Down's syndrome suppression of tumour growth and the
role of the calcineurin inhibitor DSCR1, Nature 459 (2009) 1126–1130.
[56] F. Liu, Z. Liang, J. Wegiel, Y.W. Hwang, K. Iqbal, I. Grundke-Iqbal, N. Ramakrishna,
C.X. Gong, Overexpression of Dyrk1A contributes to neurofibrillary degenera-
tion in Down syndrome, FASEB J. 22 (2008) 3224–3233.
[57] G. Arque, M.M. de Lagran, M.L. Arbones, M. Dierssen, Age-associated motor and
visuo-spatial learning phenotype in Dyrk1A heterozygous mutant mice, Neuro-
biol. Dis. 36 (2009) 312–319.
[58] F. Guedj, C. Sebrie, I. Rivals, A. Ledru, E. Paly, J.C. Bizot, D. Smith, E. Rubin, B.
Gillet, M. Arbones, J.M. Delabar, Green tea polyphenols rescue of brain defects
induced by overexpression of DYRK1A, PLoS One 4 (2009) e4606.
[59] R.X. Santos, S.C. Correia, X. Wang, G. Perry, M.A. Smith, P.I. Moreira, X. Zhu,
Alzheimer's disease: diverse aspects of mitochondrial malfunctioning, Int.
J. Clin. Exp. Pathol. 3 (2010) 570–581.
[60] E.H. Corder, A.M. Saunders, W.J. Strittmatter, D.E. Schmechel, P.C. Gaskell, G.W.
Small, A.D. Roses, J.L. Haines, M.A. Pericak-Vance, Gene dose of apolipoprotein
 I.T. Lott / Biochimica et Biophysica Acta 1822 (2012) 657–663
E type 4 allele and the risk of Alzheimer's disease in late onset families, Science
261 (1993) 921–923.
[61] A. Patel, S.D. Rees, M.A. Kelly, S.C. Bain, A.H. Barnett, D. Thalitaya, V.P. Prasher,
Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1
with dementia in Alzheimer's disease in subjects with Down syndrome, Neu-
rosci. Lett. 487 (2011) 144–148.
[62] S. Chang, T. ran Ma, R.D. Miranda, M.E. Balestra, R.W. Mahley, Huang, lipid- and
receptor-binding regions of apolipoprotein E4 fragments act in concert to cause
mitochondrial dysfunction and neurotoxicity, Proc. Natl. Acad. Sci. U. S. A. 102
(2005) 18694–18699.
[63] H.M. Abdul, R. Sultana, D.K. St Clair, W.R. Markesbery, D.A. Butterfield, Oxidative
damage in brain from human mutant APP/PS-1 double knock-in mice as a func-
tion of age, Free Radic. Biol. Med. 45 (2008) 1420–1425.
[64] W.D. Parker Jr., C.M. Filley, J.K. Parks, Cytochrome oxidase deficiency in Alzheimer's
disease, Neurology 40 (1990) 1302–1303.
[65] C. Caspersen, N. Wang, J. Yao, A. Sosunov, X. Chen, J.W. Lustbader, H.W. Xu, D. Stern,
G. McKhann, S.D. Yan, Mitochondrial Abeta: a potential focal point for neuronal
metabolic dysfunction in Alzheimer's disease, FASEB J. 19 (2005) 2040–2041.
[66] G.E. Gibson, S.S. Karuppagounder, Q. Shi, Oxidant-induced changes in mitochon-
dria and calcium dynamics in the pathophysiology of Alzheimer's disease, Ann.
N. Y. Acad. Sci. 1147 (2008) 221–232.
[67] V. Rhein, X. Song, A. Wiesner, L.M. Ittner, G. Baysang, F. Meier, L. Ozmen, H.
Bluethmann, S. Drose, U. Brandt, E. Savaskan, C. Czech, J. Gotz, A. Eckert, Amyloid-
beta and tau synergistically impair the oxidative phosphorylation system in triple
transgenic Alzheimer's disease mice, Proc. Natl. Acad. Sci. U. S. A. 106 (2009)
20057–20062.
[68] M. Corral-Debrinski, T. Horton, M.T. Lott, J.M. Shoffner, A.C. McKee, M.F. Beal,
B.H. Graham, D.C. Wallace, Marked changes in mitochondrial DNA deletion
levels in Alzheimer brains, Genomics 23 (1994) 471–476.
[69] S.V. Jovanovic, D. Clements, K. MacLeod, Biomarkers of oxidative stress are signifi-
cantly elevated in Down syndrome, Free Radic. Biol. Med. 25 (1998) 1044–1048.
[70] P.E. Coskun, J. Wyrembak, O. Derbereva, G. Melkonian, E. Doran, I.T. Lott, E. Head,
C.W. Cotman, D.C. Wallace, Systemic mitochondrial dysfunction and the etiology
of Alzheimer's disease and down syndrome dementia, J. Alzheimer's Dis. 20
(Suppl 2) (2010) S293–S310.
[71] J. Lu, G. Esposito, C. Scuderi, L. Steardo, L.C. Delli-Bovi, J.L. Hecht, B.C. Dickinson, C.J.
Chang, T. Mori, V. Sheen, S100B and APP promote a gliocentric shift and impaired
neurogenesis in Down syndrome neural progenitors, PLoS One 6 (2011) e22126.
[72] D. Valenti, G.A. Manente, L. Moro, E. Marra, R.A. Vacca, Deficit of complex I activity
in human skin fibroblasts with chromosome 21 trisomy and overproduction of
reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling
pathway, Biochem. J. 435 (2011) 679–688.
[73] G. Dogliotti, E. Galliera, E. Dozio, E. Vianello, R.E. Villa, F. Licastro, I. Barajon, M.M.
Corsi, Okadaic acid induces apoptosis in Down syndrome fibroblasts, Toxicol. in
Vitro 24 (2010) 815–821.
[74] V. Infantino, A. Castegna, F. Iacobazzi, I. Spera, I. Scala, G. Andria, V. Iacobazzi,
Impairment of methyl cycle affects mitochondrial methyl availability and gluta-
thione level in Down's syndrome, Mol. Genet. Metab. 102 (2011) 378–382.
[75] G. Aliev, Y. Li, H.H. Palacios, M.E. Obrenovich, Oxidative stress induced mitochon-
drial DNA deletion as a hallmark for the drug development in the context of the
cerebrovascular diseases, Recent patents on cardiovascular drug discovery 6
(2011) 222–241.
[76] A. Strydom, M.J. Dickinson, S. Shende, D. Pratico, Z. Walker, Oxidative stress and
cognitive ability in adults with Down syndrome, Prog. Neuro-Psychopharmacolog.
Biol. Psychiatry 33 (2009) 76–80.
[77] C. Campos, R. Guzman, E. Lopez-Fernandez, A. Casado, Urinary uric acid and
antioxidant capacity in children and adults with Down syndrome, Clin. Biochem.
43 (2010) 228–233.
[78] L. Tiano, L. Padella, P. Carnevali, O. Gabrielli, F. Bruge, F. Principi, G.P. Littarru,
Coenzyme Q10 and oxidative imbalance in Down syndrome: biochemical and
clinical aspects, Biofactors 32 (2008) 161–167.
[79] D. Il'yasova, K. Kennedy, I. Spasojevic, F. Wang, A.A. Tolun, K. Base, S.P. Young, P.
Kelly Marcom, J. Marks, D.S. Millington, M.W. Dewhirst, Individual responses to
chemotherapy-induced oxidative stress, Breast Cancer Res. Treat. 125 (2011)
583–589.
[80] J. Uberos, J. Romero, A. Molina-Carballo, A. Munoz-Hoyos, Melatonin and elimi-
nation of kynurenines in children with Down's syndrome, J. Pediatr. Endocrinol.
Metab. 23 (2010) 277–282.
[81] N.A. Meguid, A.A. Dardir, E.M. El-Sayed, H.H. Ahmed, A.F. Hashish, A. Ezzat, Homo-
cysteine and oxidative stress in Egyptian children with Down syndrome, Clin.
Biochem. 43 (2010) 963–967.
[82] L. Ji, V. Chauhan, P. Mehta, J. Wegiel, S. Mehta, A. Chauhan, Relationship between
proteolytically cleaved gelsolin and levels of amyloid-beta protein in the brains
of Down syndrome subjects, J. Alzheimer's Dis. 22 (2010) 609–617.
[83] A. Akomolafe, K.L. Lunetta, P.M. Erlich, L.A. Cupples, C.T. Baldwin, M. Huyck, R.C.
Green, L.A. Farrer, Genetic association between endothelial nitric oxide synthase
and Alzheimer disease, Clin. Genet. 70 (2006) 49–56.
[84] J.N. Sharma, A. Al-Omran, S.S. Parvathy, Role of nitric oxide in inflammatory
diseases, Inflammopharmacology 15 (2007) 252–259.
[85] A.W. Coppus, D. Fekkes, W.M. Verhoeven, S. Tuinier, J.I. Egger, C.M. van Duijn,
Plasma amino acids and neopterin in healthy persons with Down's syndrome,
J. Neural. Transm. 114 (2007) 1041–1045.
663
[86] A.M. Coppus, D. Fekkes, W.M. Verhoeven, S. Tuinier, C.M. van Duijn, Plasma
levels of nitric oxide related amino acids in demented subjects with Down
syndrome are related to neopterin concentrations, Amino acids 38 (2010)
923–928.
[87] M. Hull, G.M. Pasinetti, P.S. Aisen, Elevated plasma neopterin levels in Alzheimer
disease, Alzheimer Dis. Assoc. Disord. 14 (2000) 228–230.
[88] D. Galasko, T.J. Montine, Biomarkers of oxidative damage and inflammation in
Alzheimer's disease, Biomarkers Med. 4 (2010) 27–36.
[89] Y.X. Sun, L. Minthon, A. Wallmark, S. Warkentin, K. Blennow, S. Janciauskiene,
Inflammatory markers in matched plasma and cerebrospinal fluid from patients
with Alzheimer's disease, Dement. Geriatr. Cogn. Disord. 16 (2003) 136–144.
[90] L. Craggs, R.N. Kalaria, Revisiting dietary antioxidants, neurodegeneration and
dementia, NeuroReport 22 (2011) 1–3.
[91] R.C. Petersen, R.G. Thomas, M. Grundman, D. Bennett, R. Doody, S. Ferris, D. Galasko,
S. Jin, J. Kaye, A. Levey, E. Pfeiffer, M. Sano, C.H. van Dyck, L.J. Thal, Vitamin E and
donepezil for the treatment of mild cognitive impairment, N. Engl. J. Med. 352
(2005) 2379–2388.
[92] M.C. Morris, D.A. Evans, J.L. Bienias, C.C. Tangney, D.A. Bennett, N. Aggarwal,
R.S. Wilson, P.A. Scherr, Dietary intake of antioxidant nutrients and the risk
of incident Alzheimer disease in a biracial community study, JAMA 287
(2002) 3230–3237.
[93] M.J. Engelhart, M.I. Geerlings, A. Ruitenberg, J.C. van Swieten, A. Hofman, J.C.
Witteman, M.M. Breteler, Dietary intake of antioxidants and risk of Alzheimer
disease, JAMA 287 (2002) 3223–3229.
[94] J.A. Luchsinger, M.X. Tang, S. Shea, R. Mayeux, Antioxidant vitamin intake and
risk of Alzheimer disease, Arch. Neurol. 60 (2003) 203–208.
[95] D. Laurin, K.H. Masaki, D.J. Foley, L.R. White, L.J. Launer, Midlife dietary intake of
antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging
Study, Am. J. Epidemiol. 159 (2004) 959–967.
[96] P.P. Zandi, J.C. Anthony, A.S. Khachaturian, S.V. Stone, D. Gustafson, J.T. Tschanz,
M.C. Norton, K.A. Welsh-Bohmer, J.C. Breitner, Reduced risk of Alzheimer dis-
ease in users of antioxidant vitamin supplements: the Cache County Study,
Arch. Neurol. 61 (2004) 82–88.
[97] N. Scarmeas, Y. Stern, R. Mayeux, J.A. Luchsinger, Mediterranean diet, Alzheimer
disease, and vascular mediation, Arch. Neurol. 63 (2006) 1709–1717.
[98] C.W. Cotman, E. Head, The canine (dog) model of human aging and disease:
dietary, environmental and immunotherapy approaches, J. Alzheimer's Dis. 15
(2008) 685–707.
[99] E. Head, V. Pop, F. Sarsoza, R. Kayed, T.L. Beckett, C.M. Studzinski, J.L. Tomic, C.G.
Glabe, M.P. Murphy, Amyloid-beta peptide and oligomers in the brain and cere-
brospinal fluid of aged canines, J. Alzheimer's Dis. 20 (2010) 637–646.
[100] L. Sarasa, C. Gallego, I. Monleon, A. Olvera, J. Canudas, M. Montanes, P. Pesini, M.
Sarasa, Cloning, sequencing and expression in the dog of the main amyloid pre-
cursor protein isoforms and some of the enzymes related with their processing,
Neuroscience 171 (2010) 1091–1101.
[101] J.A. Araujo, N.H. Greig, D.K. Ingram, J. Sandin, C. de Rivera, N.W. Milgram, Cholin-
esterase inhibitors improve both memory and complex learning in aged beagle
dogs, J. Alzheimer's Dis. 26 (2011) 143–155.
[102] E. Head, V.N. Nukala, K.A. Fenoglio, B.A. Muggenburg, C.W. Cotman, P.G. Sullivan,
Effects of age, dietary, and behavioral enrichment on brain mitochondria in a
canine model of human aging, Exp. Neurol. 220 (2009) 171–176.
[103] C.W. Cotman, E. Head, B.A. Muggenburg, S. Zicker, N.W. Milgram, Brain aging in
the canine: a diet enriched in antioxidants reduces cognitive dysfunction,
Neurobiol. Aging 23 (2002) 809–818.
[104] N.W. Milgram, B. Adams, H. Callahan, E. Head, B. Mackay, C. Thirlwell, C.W.
Cotman, Landmark discrimination learning in the dog, Learn. Mem. 6 (1999)
54–61.
[105] I.T. Lott, E. Doran, V.Q. Nguyen, A. Tournay, E. Head, D.L. Gillen, Down syndrome
and dementia: a randomized, controlled trial of antioxidant supplementation,
part A, Am. J. Med. Genet. 155A (2011) 1939–1948.
[106] J.M. Ellis, H.K. Tan, R.E. Gilbert, D.P. Muller, W. Henley, R. Moy, R. Pumphrey, C.
Ani, S. Davies, V. Edwards, H. Green, A. Salt, S. Logan, Supplementation with
antioxidants and folinic acid for children with Down's syndrome: randomised
controlled trial, BMJ 336 (2008) 594–597.
[107] N.C. Berchtold, N. Castello, C.W. Cotman, Exercise and time-dependent benefits
to learning and memory, Neuroscience 167 (2010) 588–597.
[108] H. Littbrand, M. Stenvall, E. Rosendahl, Applicability and effects of physical exer-
cise on physical and cognitive functions and activities of daily living among peo-
ple with dementia: a systematic review, Am. J. Phys. Med. Rehabil. / Assoc. Acad.
Phyciatrists, 90, 2011, pp. 495–518.
[109] O. Lazarov, M.P. Mattson, D.A. Peterson, S.W. Pimplikar, H. van Praag, When neu-
rogenesis encounters aging and disease, Trends Neurosci. 33 (2010) 569–579.
[110] J.C. Zambrano, R. Marquina, N. Sulbaran, A.J. Rodriguez-Malaver, R.A. Reyes,
Aerobic exercise reduced oxidative stress in saliva of persons with Down syn-
drome, Res. Sports Med. 17 (2009) 195–203.
[111] M. Rosety-Rodriguez, I. Rosety, G. Fornieles-Gonzalez, A. Diaz, M. Rosety, F.J.
Ordonez, A 12-week aerobic training programme reduced plasmatic allantoin
in adolescents with Down syndrome, Br. J. Sports Med. 44 (2010) 685–687.
[112] K.A. Wollen, Alzheimer's disease: the pros and cons of pharmaceutical, nutri-
tional, botanical, and stimulatory therapies, with a discussion of treatment
strategies from the perspective of patients and practitioners, Altern. Med.
Rev. 15 (2010) 223–244.