Metallo-ROS in Alzheimer's disease: Oxidation of neurotransmitters by CuII-β-amyloid and neuropathology of the disease

Article abstract of DOI:10.1002/anie.200604421

A clear mind: The Cu^II-β-amyloid (Aβ) complex has been shown to exhibit enzyme-like metal-centered oxidative and hydroxylation catalyses. Metal-centered oxidation of various neurotransmitters by CuAβ under biomimetic conditions has verified the bio-relevance of the metal-centered catalyses and is expected to provide a chemical basis for the better understanding of the etiology of Alzheimer's disease. ROS = reactive oxygen species. (Figure Presented).

Full text of DOI:10.1002/anie.200604421

Angewandte
Chemie
DOI: 10.1002/anie.200604421
Alzheimer’s Disease
Metallo-ROS in Alzheimerꢀs Disease: Oxidation of Neurotransmitters
II
by Cu -b-Amyloid and Neuropathology of the Disease**
Giordano F. Z. da Silva and Li-June Ming*
The generation of reactive oxygen species (ROS), including
superoxide, peroxide, and free radicals, is associated with
normal redox metabolic pathways as side-tracks that can be
regulated through the action of superoxide dismutase, cata-
fragments CuAb1–16 and CuAb1–20 under various biomimetic
conditions.The studies described herein are expected to
provide a chemical basis for a better understanding of the
etiology of AD.
[
1,2]
lase, and some reducing agents under homeostasis.
How-
Dopamine is directly linked to the neurodegenerative
[
23]
ever, long-term effects of such oxidative chemical imbalance
in normal and disease states can be expected.ROS are often
considered the culprits responsible for the devastating effects
Parkinsonꢀs disease. As symptoms of Parkinsonꢀs disease
[
24]
are also recognized in AD patients, disturbance of dop-
amine metabolism may be closely associated with AD.
Dopamine is effectively oxidized aerobically to dopaquinone
by CuAb1–40 at pH 7.0. The rate reaches saturation at high
dopamine concentrations (Figure 1; Table 1), consistent with
enzyme-like pre-equilibrium kinetics.There is an apparent
cooperativity in the catalysis that is not usually expected in
simple monomeric systems.This may be due to the tendency
of the peptide to coagulate and/or the formation of a
dinuclear center during catalysis.Fitting the results to the
[
3]
of oxidative stress, which concern cancer, aging, heart
diseases, arthritis, diabetes, and the etiology of neurodege-
nerative disorders such as Parkinsonꢀs disease and Alzheim-
[
4]
erꢀs disease (AD). AD affects primarily the elderly and
causes considerable distress for the patients and emotional
suffering of their families and close friends.One mechanism
proposed for the neurodegeneration in AD focuses on
amyloid-b peptides (Ab) and their metal complexes through
formation of plaques and fibrils and generation of the ROS
[
25]
À4 À1
Hill equation
gives kinetic constants k = 7.48 ” 10
s
cat
[
5–9]
À1 À1
H O and free radicals.
and k /K = 2.77m
s
and a Hill coefficient q = 1.48. This
2
2
cat
m
Aggregation of Ab of 40 or 42 amino acids (DAEFR
HDSGY EVHHQ KLVFF AEDVG SNKGA IIGLM VGGVV
1
0
20
30
40
IA) in the brain is the hallmark in AD neuropathology
[
10–12]
induced by metal binding
and is usually found as metal-
containing plaques and insoluble fibrils.Similar pathological
effects are also found in transgenic mouse models with human
[
13,14]
Ab.
in vivo by insulin-degrading enzymes as well as a- and b-
Moreover, soluble fragments of Ab can be generated
[
15,16]
secretases.
Nevertheless, the cause or effect connection of
[
17–19]
the metallo-Ab plaques with AD is still under debate.
Despite immense work in Ab research, the potential risk of
metal-centered oxidative catalyses by metallo-Ab has been
[
20]
II
overlooked. The Cu complexes of metal-binding domains
of Ab (CuAb) have recently been demonstrated to exhibit
metal-centered oxidative catalysis, consistent with type-3
[
21,22]
copper oxidases.
To verify the biorelevance of this
Figure 1. Oxidation of catechol (*) and dopamine (*) by 1.47 mm
CuAb1–40 in 100 mm N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic
acid (HEPES) buffer solution at pH 7.0 and 258C. Dashed traces are
fittings to simple pre-equilibrium kinetics, whereas the solid traces are
the fittings to the Hill equation. The inset shows the effect of H O on
metal-centered catalysis, we have determined the oxidation
of several catecholamine and indoleamine neurotransmitters
catalyzed by CuAb1–40 and two metal-binding N-terminal
2
2
kcat, which indicates the presence of cooperativity.
[
*] G. F. Z. da Silva, Prof. Dr. L.-J. Ming
Department of Chemistry and Institute for Biomolecular Science
University of South Florida
[
a]
Table 1: Kinetic parameters for dopamine oxidation by CuAb.
Tampa, FL 33620 (USA)
Fax: (+1)813-974-3203
À3 À1
À1 À1
CuAb
kcat [”10
s
]
Km [mm]
kcat/Km [m
s
]
krel.
E-mail: ming@shell.cas.usf.edu
1–40
0.748
11.6
28.0
5.61
99.0
0.27
0.90
0.31
0.27
0.52
0.68
2.77
12.9
90.3
21
190
339
85
1
1
1
1
1
–20
1320
3180
312
5530
12700
[
**] The metallopeptide research is partially supported by the Petroleum
–16
Research Fund administrated by the American Chemical Society
[
b]
b]
b]
–40
(
number 40851-AC3). This Commincation is dedicated to the
[
–20
memory of Alois Alzheimer on the occasion of the centennial of the
discovery of the disease (1906–2006).
[
–16
230
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[a] In 100 mm HEPES buffer solution at pH 7.0 and 258C. [b] In the
presence of 20 mm H O .
2
2
Angew. Chem. Int. Ed. 2007, 46, 3337 –3341
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reaction shows an 85-fold rate enhancement relative to the
reaches a plateau at [H O ] > 15 mm with q = 3.57 (Figure 1,
2 2
auto-oxidation of dopamine.The shorter CuA b1–20 and
CuAb1–16 do not exhibit the apparent cooperativity and
show 16- and 37-fold, respectively, higher activities than
CuAb1–40 toward dopamine oxidation in terms of kcat.
Catechol oxidation shows the same catalytic trend (Figure 1
and Table S1 in the Supporting Information) with CuAb1–40
showing cooperativity (q = 2.7) and CuAb1–16 exhibiting the
highest activity.The results herein indicate that the soluble
CuAb fragments may be more severe in causing oxidative
stress in the brain of AD patients than the coagulation-prone
CuAb1–40.Recent studies also suggested pathological signifi-
inset), which indicates that the ROS H O can bind to CuAb
2 2
to afford a metallo-ROS in a cooperative manner.Oxidation
of catechol without the side chain by Cu-Ab1–40 exhibits a
similar kinetic pattern (Figure 1 and Table S1 in the Support-
ing Information), confirming the cooperative nature of this
oxidative catalysis.
The results conclude that metallo-ROS is much more
reactive than free ROS alone as far as H O is concerned.
2
2
Once again, the shorter CuAb1–16(20) fragments exhibit higher
activity than CuAb1–40 toward dopamine oxidation in the
presence of H O (Table 1).This observation suggests patho-
2
2
[
26]
cance of soluble forms of Ab.
logical significance of soluble Ab fragments in AD.Herein,
CuAb1–20 is able to significantly accelerate oxidation rates of
catechol and catecholamine neurotransmitters by 1350 to
Collectively termed catecholamines, dopamine, epinephr-
ine, norepinephrine, and Dopa are catechol-containing neu-
rotransmitters (while serotonin and its precursor 5-hydroxy-
tryptophan are indole-containing neurotransmitters) that are
involved in cognitive, behavioral, physical, physiological, and
5
2.24 ” 10 times in terms of k relative to k (see Table S1 in
cat
o
the Supporting Information).It is worth noting that the k /
cat
À1 À1
Km value of 1690m
s
for catechol oxidation by CuAb1–16
[
27]
psychological functions. Oxidation of these molecules may
cause severe alteration in bioactivity, eventually leading to
approaches enzyme-like catalytic efficiency, which is 5.3% of
À1 À1
the activity of the catechol oxidase (32000m s ) from
[
28]
[34]
neuronal death. Metabolic malfunctions of neurotransmit-
gypsywort (Lycopus europaeus).
[
29,30]
ters are known phenomena in the physiology of AD
have also been suggested to be related to the neuropathology
of this disease.
and
As both H O and the neurotransmitters can bind to the
2
2
metal active center, the data are analyzed with a two-
substrate random-binding mechanism according to the Hanes
[
29–32]
However, a chemical mechanism for the
[
25]
neurotransmitter malfunction in AD is still unknown.These
catecholamine neurotransmitters are found to be effectively
oxidized aerobically to their respective o-quinone products by
CuAb1–20 (see Figure S1 and Table S1 in the Supporting
Information).Herein, CuA b1–20 is able to significantly accel-
erate the aerobic oxidation rate of these neurotransmitters by
equation (see Figure S2 in the Supporting Information) to
afford the apparent and intrinsic dissociation constants KS
and K , respectively (0.34 and 0.23 for catechol and 0.52 and
Si
0.22 for dopamine, respectively). The ratios of K /K are
S
Si
greater than one, indicating that the neurotransmitters and
H O affect the binding of each other in this bisubstrate
2
2
[
25,35]
3
33–2420 times in terms of kcat relative to the auto-oxidation
reaction mechanism.
rate constant ko.
Compared with that of catechol, the auto-oxidation rates
of these neurotransmitters are nearly 10 times faster with
Ab1–40 and fragments are found in various cellular
environments, including soluble forms in the cytosol and
insoluble forms as membrane-bound plaques.Herein, the
detergent sodium dodecyl sulfate (SDS) is used to approx-
imate the amphiphilic nature of the cell membrane.Structures
of short Ab fragments in the presence of SDS differ
respect to k (see Table S1 in the Supporting Information).
o
However, their oxidation rates by CuAb are approximately
1
30- to 980-fold slower than that of catechol, reflecting their
3
higher resistance to oxidation by CuAb by approximately 10 -
considerably from that in the absence of this micelle-forming
4
[36]
to 10 -fold relative to catechol oxidation.The relatively
surfactant.
The activities of CuAbs in the presence of
higher stability against oxidative damage means that these
molecules are better suited for the purpose of neurotrans-
mission.Dopa shows a lower reactivity than other catechol-
amines, which is likely due to the inductive effect of the
carboxy group on the side chain.Chirality of these neuro-
transmitters does not appear to play a role in this oxidation
chemistry (see Table S1 in the Supporting Information).
The ROS H O has been commonly suggested to be a
micelles may offer insight into the nature of the structure and
activity of Ab.The rate constant kcat for dopamine oxidation
by CuAb1–20 is largely affected by the soluble form of SDS (4.5
times) and noticeably influenced (80%) by micelles with a
[
37]
critical micelle concentration (CMC) of around 8 mm
(Figure 2a).This pattern fits well to a binding mode with
[
38]
two different binding sites, whereas that of CuAb1–40 is only
slightly influenced by soluble SDS (2-fold) and greatly
affected by micellar SDS (8-fold).The rate constant for the
shortest CuAb1–16 is only slightly enhanced (85%) at a
saturating amount of SDS and is 14% enhanced by micelles.
Under our experimental conditions, SDS micelles do not
influence the self-oxidation rates of neurotransmitters.The
results indicate that the plaque-forming CuAb1–40 exhibits
more-significant oxidation chemistry when it is “solubilized”
and incorporated into a hydrophobic environment, whereas
the soluble CuAb1–16(20) are more powerful oxidation catalysts
than CuAb1–40 in aqueous environments (see Table S1 in the
Supporting Information).The results seem to also corrobo-
rate the “opposing-activities” proposal for neuroprotection
2
2
[
4,6]
culprit causing the oxidative stress in AD.
However, this
ROS alone, at a concentration of 50.0 mm, does not signifi-
cantly affect the oxidations of neurotransmitters (see Table S1
in the Supporting Information).Conversely, oxidations of
these neurotransmitters by CuAb in the presence of greater
[
33]
than 15 mm (> 0.051%) H O under the same conditions
2
2
exhibits significant rate enhancement (k ; see Table S1 and
rel
Figure S2 in the Supporting Information); for example, a rate
enhancement of 312-fold relative to the auto-oxidation rate
constant k for dopamine oxidation by CuAb
with kcat =
o
1–40
À1
À1 À1
0
.0056 s and k /K = 21m
s
was obtained.The oxidation
cat
m
of dopamine is dependent on the concentration of H O and
2
2
3
338
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Angewandte
Chemie
To reveal the mechanism of the full-length Ab1–40, the slow
substrate 4,5-dichlorocatechol (DCC) was titrated into a
solution of CuAb1–40.The observation of a charge-transfer
transition at 438 nm (Figure S4) is indicative of DCC binding
II
5
À1
to the Cu center (with an affinity constant of 6.4 ” 10 m , see
Figure S4 in the Supporting Information) analogous to its
[
22]
binding to the soluble CuAb1–20
.
Cooperativity is apparent
in DCC binding (see Figure S5 in the Supporting Informa-
tion), probably owing to the coagulating nature of Ab1–40.The
stoichiometry of DCC:CuAb1–40 = 1:2 verifies the dinuclear
II
Figure 2. a) Effect of SDS on the oxidative activity of CuAb1–16 (*),
CuAb1–20 (*), and CuAb1–40 (!) in 100.0 mm HEPES buffer solution at
nature of the catalysis.The activation profile during Cu
titration to Ab1–40 is sigmoidal with a Hill coefficient of q =
.68 (see Figure S5 in the Supporting Information), which
further supports a dinuclear catalysis.Cooperativity is not
usually expected in mononuclear catalysis wherein a linear
correlation of the activity with the concentration of Cu is
pH 7.0 and 258C. The data show the influence on the activity by both
the monomeric and the micellar forms of SDS with a CMC of 8 mm.
2
+
+
b) Influence of NAD(P) (*) and NAD (*) on the oxidative activity of
CuAb1–20 toward dopamine oxidation with a fixed total concentration
II
+
+
Ctot of [NAD(P) ] + [NAD(P)H]=10.0 mm. X=NAD(P) /C .
tot
expected until one equivalent is reached.
The oxidation of catecholamine neurotransmitters by
CuAb1–20 and the stoichiometry for DCC binding are con-
[
39]
through proteolysis and aggregation, wherein the highly
reactive Ab1–16(20) fragments are supposed to be eliminated by
the former process, whereas the activity of Ab1–40 is much
decreased by the latter process.The local concentrations of
[
21]
sistent with the action of dinuclear catechol oxidase. The
mechanism of this enzyme thus serves as a working model for
the metal-centered oxidation of catecholamines by CuAb.
Under aerobic conditions, the catechol moiety binds to a di-
[
4]
metallo-Ab plaques can reach the mm range, which can
cause significant oxidative damages of proximal areas on the
brain surface.Consequently, the devastating metallo-ROS
chemistry owing to CuAb1–40 and fragments in the brain of
AD patients can have a widespread effect in different cellular
environments, particularly in amphiphilic surroundings as
demonstrated herein.
II
Cu center (Figure 3, path A) and is oxidized through a two-
I
electron transfer to afford di-Cu and the o-quinone product
+
(path B).Di-Cu then binds O to form the metallo-ROS m-
2
peroxo-Cu center (paths C and D), which may bind (path E)
2
and oxidize (path F) another substrate.In the presence of an
electron donor, such as NAD(P)H (path H), the oxidation of
neurotransmitters is inhibited.Herein, H O is formed to a
+
The NAD(P) /NAD(P)H ratios (NAD = nicotinamide
2
2
adenine dinucleotide (phosphate)) vary according to changes
in metabolism and is species/tissue dependent, and thus are
certain extent that then enables production of other types of
ROS and may exacerbate the oxidative destruction by going
through the peroxide shunt (path G) upon forming the highly
[
40]
expected to affect the redox property of CuAb in vivo.
+
II
Changes in the homeostatic levels in terms of NAD(P) /
reactive metallo-ROS m-peroxo-di-Cu intermediate.The
NAD(P)H may reflect the neurochemical status under
metal-bound H O as a metallo-ROS in equilibrium with
three isoelectronic species (path D) has been demonstrated
2
2
[
42]
[45]
oxidative stress. Metabolic changes have been noted to be
associated with several age-related diseases, including neuro-
[
41]
degenerative diseases. It has been previously reported that
these ratios are managed according to spatial and temporal
[
42]
constraints in the brain when under oxidative stress. The
oxidation activity of CuAb1 is lowered by NAD(P)H.As
–20
+
the ratios of NAD(P) /NAD(P)H decrease, the activity in
terms of kcat toward dopamine oxidation decreases by 2.4 and
1
.9 times, respectively (Figure 2b). Based on the proposed
[
21]
mechanism for catechol oxidation by Cu-Ab1–20
,
the
inhibitory effect of NAD(P)H is due to a shift in equilibrium
[
21,40]
toward H O generation under reducing conditions.
The
2
2
more pronounced inhibition caused by NADPH as compared
with NADH might be attributed to the phosphate group in
NADPH.Indeed, phosphate has been observed to be a
competitive inhibitor toward the oxidation of dopamine, with
K = 4.7 mm (see Figure S3 in the Supporting Information).
i
+
The ratio of free NAD /NADH has been under debate,
nevertheless, it has recently been suggested to be around
00, which is consistent with the value based on potentio-
metric measurement. The relatively smaller availability of
the free form of NADH suggests that this biological reducing
agent may not significantly influence the metal-centered
oxidative catalysis of CuAb under physiological conditions.
[
43]
6
[
44]
Figure 3. Mechanism for the oxidation of catecholamine neurotrans-
mitters and the cause of neurodegeneration by CuAb. The metal-
bound H O as a “metallo-ROS” is shown in path D.
2
2
Angew. Chem. Int. Ed. 2007, 46, 3337 –3341
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3339

Communications
herein to be a more potent oxidative agent to cause neuro-
degeneration than H O alone.
Oxidation of catecholamines is known to generate neurotoxic
[
49]
quinone products that are involved in protein modification
2
2
[
50]
The plaque-forming CuAb1–40 also shows significant
metal-centered oxidative activity toward the relatively more
inert phenol (see Figure S6a and Table S1 in the Supporting
(e.g., covalent modification of dopamine transporter ) and
[
51]
polymerizing tau protein into fibrils. Age-related deficien-
cies of both dopamine and norepinephrine have been
implicated in the vulnerability of noradrenergic neurons in
À1
Information), showing kcat = 0.439 and 1.43 s (with q = 1.6)
À1 À1
[52]
and k /K = 0.351 and 1.14m
s
in the absence and
the hippocampus, which suffers significant damage in AD.
cat
m
presence of 50.0 mm H O , respectively.The activity reaches
Moreover, loss of noradrenergic neurons is linked to degra-
dation of the locus ceruleus, which is rich in dopaminergic
2
2
saturation at high H O concentrations (see Figure S6b in the
2
2
[
53]
Supporting Information), reflecting binding of H O to the
neurons that show severe lesions in AD. Hence, a possible
mechanism for reduction in neurotransmitter-regulated alert-
ness response, delay-period activity, sleep cycle, mood
stabilization, short-term memory, cognition, attention and
problem-solving capability, satisfaction feeling, and coordi-
nation of physical movement experienced by AD
2
2
metal to afford metallo-ROS.Phenol hydroxylation and
oxidation exhibits the same trend of reactivity with the
shortest CuAb1–16 showing the highest activity (see Table S1 in
the Supporting Information).Herein, oxidation of phenol is
6
5
dramatically enhanced by 6.64 ” 10 and 1.41 ” 10 times by
[
29–32]
CuAb1–16 with and without 50.0 mm H O , respectively.
patients
may be due to excessive oxidation of neuro-
2
2
Serotonin can be hydroxylated and oxidized into its
transmitters, hinting at a possible neuropathological role of
metallo-ROS associated with CuAb.
quinone form by CuAb with significant rate enhancements
4
3
5
ranging from (324–3.03 ” 10 )-fold and (8.41 ” 10 –2.69 ” 10 )-
In conclusion, the plaque-forming CuAb1–40 and frag-
ments thereof have been demonstrated to exhibit significant
activities toward the oxidation of neurotransmitters with or
without H O , which presumably can be further enhanced by
fold relative to k without and with more than 50 mm H O ,
o
2
2
respectively (Figure 4 and Table S1 in the Supporting Infor-
mation).As in the case of catecholamine oxidation, the
oxidation of serotonin by CuAb1–40 is slower than that by
CuAb1–(16,20).The serotonin precursor 5-hydroxy-Trp can also
be effectively hydroxylated and oxidized (see Table S1 in the
Supporting Information).The apparent and intrinsic dissoci-
ation constants K and K for phenol are determined to be
2
2
interacting with membranes.The results suggest that an
imbalance of neurotransmitter metabolism can be created
near Ab1–40 plaques in AD.The results also suggest that small
fragments of Ab, owing to their soluble nature, can signifi-
cantly disturb neurotransmission in a more systematic manner
in the brain of AD patients and thus may play an important
role in neuropathology of this devastating disease.
S
Si
1
.23 and 0.54 mm, respectively, from the Hanes plots, indicat-
ing that H O binds to the metal center and decreases the
2
2
[
25,35]
binding of serotonin.
The hydroxylation/oxidation reac-
[
46]
tions seem to follow the tyrosinase mechanism. However,
II
Cu -Ab is still highly active in the hydroxylation reaction Experimental Section
II
even without H O , whereas the di-Cu Met form of
Ab1–16(20) were synthesized at the Peptide Center of the University of
South Florida and confirmed with a Bruker MALDI-TOF mass
2
2
tyrosinase is not.The large oxidation enhancements of the
two indoleamines suggest that their oxidation by CuAb,
possibly taking place in the brain of AD patients, may alter
serotonin-mediated physiological functions, including sleep
disorders, mood changes, and anxiety often associated with
spectrometer.A b1–40 was purchased from Biopeptide Co., LLC (San
II
Diego, CA).The Cu complex of Ab1–40 was prepared according to
[54]
literature procedures
and the concentration determined with a
standard (bicinchoninic acid) BCA assay.The CuA b stock solutions
were quickly divided up into aliquots to prevent concentration
deviations caused by aggregation.
[
47]
AD patients.
Cell-culture experiments reveal that catecholamines can
Kinetic measurements were performed and analyzed as previ-
[
21,22]
À1
À1
[
48]
ously described
(eproduct = 32500m cm for phenol and cate-
exacerbate the oxidative stress caused by Ab, wherein the
[
55]
À1
À1
[
20]
chol and 28900, 27200, and 27500m cm for Dopa, dopamine,
[56]
metal-centered oxidative catalysis has been overlooked.
À1
À1
and epinephrine/norepinephrine, respectively, and 35200m cm
for serotonin and 5-hydroxytryptophan).The data were analyzed with
the bisubstrate Hanes plot for experiments in the presence of H O to
2
2
yield the apparent K and intrinsic K dissociation constants for the
S
Si
[
25]
neurotransmitters and H O .
2
2
Received: October 28, 2006
Revised: December 26, 2006
Published online: March 22, 2007
Keywords: Alzheimer’s disease · copper · oxidoreductases ·
.
peptides · redox chemistry
Figure 4. a) Aerobic oxidation of serotonin by 1.47 mm CuAb1–40 in
1
00.0 mm HEPES buffer solution at pH 7.0 and 258C. Dashed traces
are fittings to pre-equilibrium kinetics, whereas the solid traces are
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2
2
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Angewandte
Chemie
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