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Serial Review
Copper Biology in Health and Disease
Guest Editor: Hirokazu Hara
The accumulation of copper in the brain of
Down syndrome promotes oxidative stress:
possible mechanism underlying cognitive
impairment
Keiichi Ishihara*
Department of Pathological Biochemistry, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan
(Received 1 December, 2021; Accepted 29 December, 2021; Released online in J-STAGE as advance publication 15 February, 2022)
Individuals with Down syndrome (DS), which is caused by
triplication of human chromosome 21 (Hsa21), show numerous
characteristic symptoms, such as intellectual disability, an impaired
cognitive function, and accelerated aging-like phenotypes.
Enhanced oxidative stress is assumed to be implicated as a
mechanism underlying many of these symptoms of DS. Some
genes coded in Hsa21, such as App, Sod1, and Ets2, are suggested
as being involved in the exacerbation of oxidative stress. In
addition, enhanced oxidative stress has been recently shown to
be caused by dyshomeostasis of the redox-active bio-metal
copper in the brain of a mouse model of DS. This review aims to
summarize the current knowledge on enhanced oxidative stress in
DS and suggest a possible molecular mechanism underlying
the cognitive impairment of DS mediated by enhanced oxidative
stress.
Key Words:Down syndrome, oxidative stress, copper, cognitive
impairment
Down syndrome (DS), caused by triplication of human
chromosome 21 (Hsa21), is the most frequent aneuploidy,
occurring in approximately 1 in 700 live births.(1) DS is charac‐
terized by developmental retardation, intellectual disability,
craniofacial abnormalities, and hypotonia.(2) Most individuals
with DS exhibit mild to moderate learning disability. Overexpres‐
sion of some Hsa21 genes, such as amyloid precursor protein
(APP),(3) regulator of calcineurin-1 (RCAN1),(4,5) dual-specificity
tyrosine phosphorylation regulated kinase 1A (DYRK1A),(6)
synaptojanin 1,(7) and single-minded homolog 2,(8) has been
suggested to be associated with learning and memory defects in
mice. Therefore, gene-dosage imbalance of Hsa21 genes due to
triplication is considered a major cause of learning anomalies in
individuals with DS.(9,10)
The Hsa21 genes suggested to be involved in cognitive impair‐
ment have been identified through investigations using transgenic
mice, and the candidate genes have been shown to be expressed
at extremely high levels. However, the contribution of each gene
to the cognitive impairment in DS is believed to be limited,
suggesting that triplication of several Hsa21 genes may partici‐
pate in cognitive impairment cooperatively.
It is widely accepted that enhanced oxidative stress (OS) can
lead to cognitive impairment. Indeed, increased levels of lipid
peroxidation products have been detected in models of vascular
dementia and Alzheimer’s disease (AD), which exhibit cognitive
impairment.(11) Enhancement of OS is caused by the increased
production of reactive oxygen species (ROS) and reactive
nitrogen species (RNS) and/or a decreased ROS/RNS scavenging
ability. The overproduction of ROS has been shown in neuronal
cells obtained from DS fetuses.(12) Erythrocytes from DS
individuals show significantly higher levels of malondialdehyde
(MDA), a typical product of lipid peroxidation, than controls.(13)
Furthermore, mitochondrial dysfunction and the overproduction
of ROS are detected in fibroblasts from human fetuses with
DS.(14) In addition, evidence of enhanced OS in mouse models of
DS has been accumulated.(15–17)
In this review, we will discuss the molecular mechanisms
underlying the enhanced OS in DS models and the possibility of
cognitive impairment in DS caused by enhanced OS.
Hsa21 Genes Associating with Enhanced OS
Several genes coded in Hsa21 are suggested to be associated
with enhanced OS in DS (Fig. 1). The increased expression of
superoxide dismutase 1 (SOD1) is one particularly promising
candidate potentially involved in enhanced OS. The overexpres‐
sion of SOD1 results in the overproduction of H2O2. Normally,
H2O2 is catabolized into H2O by catalase (CAT) and glutathione
peroxidase (GPX), but the copy number of these genes are
normal. Thus, increasing the expression of SOD1 without
increasing the expression of CAT and GPX may lead to the accu‐
mulation of hydrogen peroxide in DS. Supporting this hypoth‐
esis, an increased ratio of SOD1 to [CAT + GPX] and enhanced
lipid peroxidation have been shown in fibroblasts derived from
fetuses with DS and erythrocytes from children with DS.(18,19)
The APP gene coded in Hsa21 is also suggested to be involved
in mitochondrial dysfunction in DS. The increased expression
of APP in mitochondria results in the progressive accumulation
of transmembrane-arrested APP and causes mitochondrial
dysfunction and impaired energy metabolism, suggesting that
*To whom correspondence should be addressed.
E-mail: ishihara@mb.kyoto-phu.ac.jp
doi: 10.3164/jcbn.21-155
©2022 JCBN
J. Clin. Biochem. Nutr. | July 2022 | vol. 71 | no. 1 | 16–21
the overexpression of APP may enhance OS via mitochondrial
dysfunction in DS.(20)
The involvement of Hsa21 genes other than App and Sod1 in
enhanced OS has also been suggested. Ts1Cje mice, a model of
DS carrying an extra copy of mouse chromosome 16 (Mmu16),
which is orthologous to Hsa21, shows enhanced OS in the brain,
although the trisomic region of the Ts1Cje mouse does not
include the Sod1 gene.(15,17) In the trisomic region of Ts1Cje mice,
the Rcan1, Ifnar2, Ifnar1, Ifngr2, and Ets2 genes have shown
potential association with enhanced OS in DS. RCAN1-deficient
neurons display an increased resistance to damage by H2O2,
suggesting that RCAN1 increases neuronal susceptibility to
OS.(21) Neurons accumulating chronically RCAN1 longer isoform
1, which is highly expressed in the central nervous system with
DS, promote OS-induced apoptosis with caspase-3 activation.(22)
Increasing the copy number of interferon receptor genes in
Mmu16, Ifnar2, Ifnar1, and Ifngr2 is assumed to result in the
overactivation of Jak-Stat signaling in response to type I inter‐
feron.(23) It has been shown that type I interferon signaling is
activated in the aged brain and correlates with increased OS.(24)
The overexpression of ETS2 in human cortical neurons with DS
is suggested to promote neuronal apoptosis through mitochon‐
Sod1
App
Hsa21
Mmu16
Lipi
Ifnar1
Ifngr2
: Activate JAK/STAT pathway (response to IFNα/β)
Ifnar2
miR802
Ets2
: Scavenges superoxide radicals (producing H2O2)
: Activates JNK and p38 MAPK pathways
: mitochondrial dysfunction and impaired energy metabolism
Rbm11, Hspa13, Samsn1, Nrip1, Usp25, Cxadr, Btg3, D16Ertd472e, Chodl,
Tmprss15, Ncam2, miR-155, Mrpl39, Jam2, Gabpa
Cyyr1, Adamts1, Adamts5, N6amt1, Ltn1, Rwdd2b, Usp16, Cct8, Map3k7cl, Bach1,
Grik1, Cldn17, Cldn8, KRTAP cluster, Tiam1
Scaf4, Hunk, Mis18a, Mrap, Urb1, Eva1c, Synj1, Paxbp1, Olig2, Olig1
Il10rb
: Promotes the activation of a mitochondrial death pathway
Tmem50b, Dnajc28, Gart, Son, Donson, Cryzl1, Slc5a3, Mrps6, Kcne2,
Smim11, Kcne1, Rcan1, Clic6, Runx1
Setd4, Cbr1, Cbr3, Dopey2, Morc3, Chaf1b, Cldn14, Sim2, Hlcs, Ripply3, Pigp,
Ttc3, Dscr3, Dyrk1a, Kcnj6, Kcnj15, Erg
Psmg1, Brwd1, Hmgn1, Wrb, Lca5l, Sh3bgr, B3galt5, Itgb2l, Igsf5, Pcp4,
Dscam, Bace2, Fam3b, Mx2, Tmpss2, Ripk4, Prdm15, C2cd2, Zbtb21
Trisomic region of Ts1Cje mouse
Fig. 1. Genes coded in Mmu16 syntenic to Hsa21 and annotated genes possible involved in enhanced OS. The region of Mmu16 from Lipi to
Zbtb21 is syntenic to a large portion of Hsa21. Annotated genes in the Mmu16 syntenic to Hsa21, which are suggested to be involved in enhanced
oxidative stress, are presented in large letters.
K. Ishihara J. Clin. Biochem. Nutr. | July 2022 | vol. 71 | no. 1 | 17
©2022 JCBN
drial dysfunction.(25) In addition to the protein-coding gene in
Mmu16, miR-802 is also coded in the trisomic region of Ts1Cje
mice. miR-802 is suggested to activate the JNK and p38 MAPK
pathways and induce hepatic OS.(26) Although the triplication of
such protein-coding genes and this miRNA may cooperatively
enhance OS in DS, the mechanisms underlying the enhanced OS
in DS remain unclear.
Enhanced OS is suggested to associate with cognitive impair‐
ment in DS. Indeed, experiments using mouse models of DS
have demonstrated that reducing OS via vitamin E treatment
improved the cognitive impairment in Ts65Dn mice carrying a
trisomic region that was longer than that in Ts1Cje mice.(16,27)
Unfortunately, antioxidants have shown no efficacy on the
impaired cognitive function of adult humans with DS;(28,29)
however, the involvement of several issues, such as low transi‐
tivity into the brain, has been considered. Further clinical trials
may demonstrate the effectiveness of supplements with improved
antioxidant efficacy on DS-induced cognitive impairment.
Accumulation of Copper in the Brain of Ts1Cje Mice
As mentioned above, the association of certain Hsa21 genes
with enhanced OS in DS has been mostly suggested based on
observations obtained in overexpression experiments. While
several Hsa21 genes may cooperatively exacerbate OS, other
factors might also be involved in the enhanced OS in DS. Redox-
active biometals, such as iron and copper, play a role in oxidative
metabolism.(30) Dyshomeostasis of Fe(II/III) and Cu(I/II) may
promote OS in DS. Indeed, the copper concentration in red blood
cells was shown to be higher in people with DS than in age- and
sex-matched controls without DS.(31)
Although iron promotes the release and metabolism of
dopamine and other neurotransmitters,(32) excessive iron promotes
ROS production through the Fenton reaction, which causes
protein oxidation, lipid peroxidation, and DNA damage.(33)
Abnormal iron concentrations have not yet been shown in the
brains of DS patients, but increased levels of non-protein-bound
iron and a slight reduction in the total serum iron content have
been detected in both plasma and erythrocytes of people with
DS.(34) Furthermore, an increase in the level of non-protein-bound
iron was shown to be correlated with increased lipid peroxidation
and cognitive decline.(35)
In addition to iron, copper is also biochemically redox active.
Copper induces OS through two possible mechanisms: the
Fenton reaction and downregulation of glutathione.(36) In the rat
brain, copper-overload induces oxidative damage via decreased
levels of glutathione and increased levels of MDA, a typical lipid
peroxidation product.(37) Thus, copper plays a key role in the
induction of OS of the brain. It has been shown that the copper
content is increased in erythrocytes and the tongue muscles of
individuals with DS,(38,39) suggesting that the overall copper level
was increased; however, the number of samples in those studies
was limited, and no studies have analyzed brain tissue, even in
mouse models. Therefore, we measured the amounts of biogenic
elements in the brain of the Ts1Cje, a mouse model of DS. Induc‐
tively coupled plasma mass spectrometry (ICP-MS) revealed
elevated concentrations of copper in the brain of Ts1Cje mice.(40)
Furthermore, we demonstrated that enhanced OS (as assessed by
lipid peroxidation) and reduced anxiety-like behaviors were
improved in Ts1Cje mice fed a low-copper diet.(40) Thus, the
accumulation of copper in the brain of Ts1Cje mice seems to
have caused enhancement of OS and reduced anxiety behaviors.
Regarding the relationship between decreased anxiety and
enhanced OS, Hovatta et al.(41) identified several genes with a
differential expression among six inbred mice. Among these
genes, they found that increased activities of two antioxidant
genes, glyoxalase-1 (Glo1) and glutathione reductase-1, were
associated with increased anxiety in mice.(41) In contrast, it has
also been suggested that the expression of Glo1 may reflect the
anxiety level, with a high Glo1 expression indicating a low
anxiety level.(42) Although controversial observations have been
reported, anxiety seems to have a profound connection with OS.
Possibility of Cognitive Impairment by a High
Concentration of Copper in the Brain
Wilson’s disease, which is an inherited disorder induced by the
accumulation of copper in the liver, brain, and other organs, is
characterized by memory impairment and depression.(43) Further‐
more, perturbations in brain concentrations of copper and zinc
are suggested to underlie the pathoetiology of AD.(44,45) It has also
been noted that individuals fed a diet high in saturated and trans
fats who have high copper levels develop cognitive decline at a
faster rate than others.(46) These observations suggest that a
disturbed copper concentration in the brain can impair the cogni‐
tive function.
The accumulation of hyperphosphorylated tau has been shown
in mouse models of DS,(15,47) such as Ts1Cje and Tc1 mice, which
carry an almost complete, freely segregating copy of Hsa21.(48)
Dyrk1a has been suggested to be a candidate for hyper‐
phosphorylated tau deposition in multiple studies.(49–51) An in
vitro study demonstrated that tau is phosphorylated at Thr212
—which is suggested to be associated with the pathogenesis of
AD—by DYRK1A.(49,52,53) A recent study found that enhanced
OS negatively affected the function of protein phosphatase 2A
(PP2A) through the modification of 4-hydroxy-2-nonenal (4-
HNE), resulting in a reduction in the dephosphorylation of hyper‐
phosphorylated tau in Ts65Dn mice.(54) Calcineurin, known as
protein phosphatase 2B (PP2B), also dephosphorylates hyper‐
phosphorylated tau protein.(55) Inhibition of calcineurin by
RCAN1 overexpression in DS may contribute to the accumula‐
tion of hyperphosphorylated tau.
Copper promotes hyperphosphorylation and the aggregation of
tau protein.(56) In addition, high copper accumulation has been
detected in neurofibrillary tangles (NFTs).(57) In hTau mice
expressing wild-type human tau and lacking endogenous mouse
tau, exposure to high amounts of copper increased tau hyper‐
phosphorylation without the accumulation of Aβ and induced the
impairment of spatial learning and memory.(58) Thus, the accumu‐
lation of copper in the brain with DS may lead to cognitive
impairment via tau hyperphosphorylation.
Consistently, hyperhoshorylated tau accumulates in the
hippocampus of Ts1Cje mice overexpressing DYRK1A.(15) Given
our recent results showing that the accumulation of copper causes
enhanced OS and the accumulation of hyperphosphorylated tau
in Ts1Cje mice,(40) several genes coded in the trisomic region of
Ts1Cje appear to enhance OS through the accumulation of
copper, and the enhanced OS then induces the accumulation of
4-HNE-adducted PP2A. 4-HNE-modification would decrease
the activity of PP2A, resulting in decrease of dephosphorylation
of the hyperphosphorylated tau (Fig. 2). The trisomic region of
the Ts1Cje mouse model codes no genes, which is suggested to
associate with copper metabolism, so we assume that gene X
indirectly upregulates the concentration of copper in the brain of
DS individuals (Fig. 2).
Conclusions
Enhanced OS may be involved in the pathophysiology of
various DS anomalies, including cognitive dysfunction. We
showed that the accumulation of copper causes enhanced OS in
the brain of Ts1Cje mice, a DS mouse model.(40) Although
clinical trials concerning treatment with the antioxidant vitamin
E for cognitive impairment in individuals with DS have been
performed in elderly people with DS, no beneficial effects on the
progression of cognitive deterioration have been detected.(28) As
18 doi: 10.3164/jcbn.21-155
©2022 JCBN
shown in Fig. 2, OS enhanced by the accumulation of copper and
disturbance of the tau kinase DYRK1A and the tau phosphatases
PP2A and PP2B lead to the accumulation of hyperphosphory‐
lated tau in the brain. This may be involved in the early onset of
AD-like dementia in individuals with DS. Taken together, these
findings suggest that copper is a promising target for pharma‐
cotherapy of the cognitive impairment characteristic of DS, and
indeed, a copper chelator has already been used to treat patients
with Wilson’s disease.
Acknowledgments
This work was supported, in part, by the JSPS KAKENHI
25460077 (to KI), 18K06940 (to KI) and 20H05521 (to KI); and
by the Ministry of Education, Science, Culture, and Sports of
Japan, Strategic Research Foundation Grant-aided Project for
Private Universities from the Ministry of Education, Culture,
Sport, Science, and Technology, Japan (MEXT), No. S1201008,
and Takeda Science Foundation 2016 (to KI).
Trisomy
21
SOD1
O2–
superoxide
H2O2
Gene X
CAT GPX
PRX
H2O
·OH + OH–
Cu+
Cu2+
Enhanced OS
Mitochondrial
dysfunction
App
Sod1
Ets2
4-HNE
Rcan1
PP2B (calcineurin)
Dyrk1a
PP2A
modification
4-HNE
function
RCAN1
Microtuble
tau
P
D
YRK1A
Impairment of memory and learning
P
P
O
OH
Fig. 2. Possible mechanisms underlying exacerbation of OS and the accumulation of phosphorylated tau in the brain of DS subjects. In DS brain,
the gene-dosage-dependent increased expression of APP and ETS2 is suggested to lead to mitochondrial dysfunction and generate ROS, such as
superoxide. The expression of SOD1 is also increased in a gene-dosage-dependent manner. An increased level of SOD1 leads to the production of
H2O2. Gene X in Hsa21, which causes the accumulation of copper in the brain with DS, induces the production of hydroxy radicals, and the
resulting enhanced OS produces 4-HNE through lipid peroxidation. Intercellular protein phosphatase 2A (PP2A), which dephosphorylates phospho‐
rylated tau, is modified by 4-HNE and reduces its function. The DYRK1A level is upregulated in DS due to increased copy numbers. Since DYRK1A
phosphorylates tau protein, the accumulation of phosphorylated tau in the DS brain is promoted. The increased expression of RCAN1 inhibits the
activity of calcineurin (PP2B), which also dephosphorylates Tau protein. The accumulation of hyperphosphorylated tau in the DS brain may cause
the impairment of memory and learning. A dashed arrows means a suppressed influences over the reaction.
K. Ishihara J. Clin. Biochem. Nutr. | July 2022 | vol. 71 | no. 1 | 19
©2022 JCBN
Abbreviations
AD Alzheimer’s disease
APP amyloid precursor protein
CAT catalase
DS Down syndrome
DYRK1A dual-specificity tyrosine phosphorylation regulated
kinase 1A
Glo1 glyoxalase-1
GPX glutathione peroxidase
Hsa21 human chromosome 21
4-HNE 4-hydroxy-2-nonenal
ICP-MS inductively coupled plasma mass spectrometry
MDA malondialdehyde
Mmu16 mouse chromosome 16
NFTs neurofibrillary tangles
OS oxidative stress
PP2A protein phosphatase 2A
PP2B protein phosphatase 2B
RCAN1 regulator of calcineurin-1
RNS reactive nitrogen species
ROS reactive oxygen species
SOD1 superoxide dismutase 1
Conflict of Interest
No potential conflicts of interest were disclosed.
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