Article

Luteinizing hormone modulates cognition and amyloid-deposition in Alzheimer APP transgenic mice

Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 05/2006; 1762(4):447-52. DOI: 10.1016/j.bbadis.2006.01.008
Source: PubMed
ABSTRACT
Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

Full-text

Available from: Craig S Atwood
Luteinizing hormone modulates cognition and amyloid-β deposition in
Alzheimer APP transgenic mice
Gemma Casadesus
a
, Kate M. Webber
a
, Craig S. Atwood
b
, Miguel A. Pappolla
c
,
George Perry
a
, Richard L. Bowen
d
, Mark A. Smith
a,
a
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA
b
School of Medicine, University of Wisconsin and William S. Middleton Memorial Veterans Administration, Madison, WI 53705, USA
c
Department of Neuroscience, LSU Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
d
Voyager Pharmaceutical Corporation, Raleigh, NC 27615, USA
Received 17 August 2005; received in revised form 17 January 2006; accepted 18 January 2006
Available online 13 February 2006
Abstract
Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological
studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases
the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamicpituitary
gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is
elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-β protein precursor. Therefore, in this study, to
evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide
acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-β
deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased
amyloid-β deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-β correlated with
improved cognition. Since both cognitive loss and amyloid-β deposition are features of Alzheimer disease, leuprolide acetate treatment may prove
to be a useful therapeutic strategy for this disease.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Alzheimer disease; Amyloid-β; Cognition; Hippocampal function; Luteinizing hormone; Therapeutics
1. Introduction
Various lines of evid ence suggest the involvement of
menopause a nd age-related testosterone d ecline-induced
changes in hypothalamicpituitarygonadal (HPG) axis hor-
mone levels in the etiology of Alzheimer disease (AD)
(reviewed in [1]). Declines in sex steroids have long been
associated with AD incidence and prevalence [2] and hormone
replacement therapy (HRT) linked to a decreased risk of
developing AD [3,4]. However, recent findings, reporting
negative cognitive effects following HRT in women at an AD-
vulnerable age [57]. Alternative theories also involve the role
of free testosterone and high sex hormone-binding globulin
(SHBG) levels in the disease such that reduced testosterone
levels, as those found in women, and increased levels of SHBG,
as those found in HRT takers, which result in reduced free
testosterone, may account for the higher incidence of disease in
women [810]. Nevertheless, changes in estrogen and testos-
terone do not account for why men with Down's syndrome have
a significantly higher risk for developing AD-type changes than
women since the levels of sex steroids in individuals with
Down's syndrome are comparable to those found in the general
population [11,12]. This phenomenon indicates that hormones
other than estrogen or testosterone per se may be important.
Interestingly, in Down's syndrome individuals have higher
levels of gonadotropins such as LH [13], and more importantly,
men have higher level s of luteinizing hormone (LH) than do
Biochimica et Biophysica Acta 1762 (2006) 447 452
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Page 1
age-matched women [11], whereas the opposite is found in the
general population (i.e., higher levels of LH in women than in
men of the same age [14]). Therefore, LH represents the only
factor, thus far, that explains the gender predispositi on in the
incidence of AD as well as its reversal in Down's syndrome
[15]. Supporting this view, individuals with AD have a two-fold
elevation in LH serum concentrations when compared to age-
matched controls [14,16]. However, two recent studies reported
no elevation of LH in AD [17,18]. This disparity in results likely
reflects the different ages and grouping techniques used across
the studies. This aspect aside, it is important to note that
gonadotropin (LH)-based etiopathogenic etiology of AD is
supported by several other pieces of evidence. First, questions
regarding a critical period of HRT-based protection against
dementia [19,20] suggest that members of the HPG axis other
than sex steroids could be involved. In this regard, the levels of
LH are highest during the peri-menopause and early meno-
pausal periods [21] and it is notable that HRT du ring this period,
which by increasing estrogen would lower LH levels, has been
observed to be most succ essful at preventing dementia.
Secondly, in the brain, likely due to the fact that LH can cross
the blood brain barrier freely [22,23], patients with AD show
increased levels of LH in topographical locations that mirror the
selective and vulnerable neuronal populations [24]. This latter
finding likely relates to the fact that the highest density of LH
receptors in the brain are found within the hippocampus [22],a
region that is particularly vulnerable in AD, and the
degeneration of which leads to early memory loss in the disease
([25,26] for review). In early studies, suggestive of a key role of
LH in AD pathogenesis, we showed that LH drives amyloid-β
protein precursor (AβPP) processing towards the amyloido-
genic pathway in vitro [27]. These findings indicate that
gondadotropins such as LH may play an important role in the
onset and progression of AD. Therefore, the aim of this study
was to e xamine the capacity of a gonadotropin-re leasing
hormone agonist, leuprolide acetate, which abolishes the release
of LH [27,28], to modulate cognitive performance and amyloid-
β deposition in the brains of aged Tg2576 mice carrying the
Swedish APP mutation. Aged females as opposed to younger
females were used to attempt to mimic the capacity of this drug
to modulate advanced stages of AD.
2. Materials and methods
2.1. Animals
We used female 21 month-old non-cycling transgenic mice Tg2576 that
over-express the 695-amino-acid isoform of human AβPP containing a
Lys670 Asn, Met671 Leu mutation found in a Swedish family with
early onset AD. In these animals, levels of amyloid-β begin to rise in the brain
by 6 months of age and by 910 months they develop senile plaque-like
deposits of amyloid-β [29]. All animals were genotyped using a standard PCR
protocol [29]. All animals were group housed (n = 3/cage), provided ad libitum
access to food and water, and maintained on a 12 h light/dark cycle. The
experimental groups were chosen in a random fashion and received leuprolide
acetate [7.5 mg/kg, slow release (depot) formulation] (n = 8) or physiological
0.9% saline (n = 5) injected intra-muscularly (IM) twice monthly for a duration of
3 months and all measurements (behavioral/immunocytochemical) were carried
out by the observer blind to the treatment. All animals were weighed 3 times
during the study and showed no significant weight loss across groups or time. All
animals were in good health with no obvious signs of disease, however, four
animals died during the course of the study. Weight and death data are
summarized in Table 1. We have previously shown that this dose regimen
successfully abolishes LH levels in these mice [27].
2.2. LH measurements
Additional animals (n=4/group) of the same age, genotype, gender, and
handling to animals tested for behavior were used to determine treatment
efficacy of leuprolide acetate on LH serum levels. Blood samples were taken
upon sacrifice, centrifuged to collect serum, and LH levels were measured
by RIA analysis (Dr. Nett-ARBL-Endocrine Laboratory, Colorado State
University).
2.3. Y-maze procedure
We used the Y-maze task (32 cm × 10 cm × 26 cm) to measure spontaneous
alternation behavior, a cognitive parameter [30] previously used by others to
measure effectiveness of potential treatments in animal models of AD [3133]
as well as exploratory activity. Each animal was tested prior to treatment (age 21
months) and at the end (age 24 months). As previously described [31], animals
were placed in one of three arms of the maze chosen at random across trials, and
left to explore all arms of the maze for 5 min during which time the sequence and
number of arm choices were recorded. Spontaneous alterations were expressed
as a percentage and referred to as the proportion of arm choices that differed
from previous choices [34].
2.4. Amyloid-β immunohistochemistry and quantification
For amyloid-β immunohistochemistry, animals were sacrificed with a lethal
dose of pentobarbital and their brains removed and fixed in 4% paraformal-
dehyde. All brains were simultaneously sagitally sectioned (50 μm) across the
hippocampus to ensure accurate region sectioning and quantification [35].
Sections were stained free-floating; after a H
2
O
2
treatment and blocking serum,
sections were immunostained with a primary amyloid-β antibody (4G8, which
recognizes the sequence of amyloid-β in the 1724 region) (0.164 mg/ml)
(1:5000 mouse monoclonal) for 24 h (at 4 °C), a goat anti-mouse secondary
antibody for 30 min at RT, and avidinbiotinHRP complex (Vectastain Elite
ABC kit, Vector, Burlingame, CA) for 1 h RT. Sections were developed with
diaminobenzidine tetrahydrachloride (DAB) with H
2
O
2
and mounted on glass
slides.
Quantification of amyloid-β deposition was carried out using a Zeiss
Axiocam (Munchen-Hallbergmoss, Germany) and compatible image analysis
software, KS300 (Carl Zeiss Vision GmbH, Munchen-Hallbergmoss, Germany).
For each animal, every 6th section of a series through the dorsal hippocampus
(approximately 240 μm apart) was selected (approximately 11 sections/animal)
and quantified for amyloid-β deposition as previously described [36]. Briefly,
using a objective, a single field encompassing the entire hippocampus was
manually selected and positive staining was expressed as the percent area
stained across the area. The values obtained from all sections per animal were
averaged.
2.5. Statistical analysis
Using appropriate software (Sigmastat, SPSS-Inc., Chicago, IL), a two-way
repeated measures ANOVA was used to determine differences in Y-maze
alternation behavior across treatment groups (leuprolide acetate vs. saline) and
Table 1
Weight and animal death information
Number of animals Weight (g)
Baseline 3 months Baseline 3 months
Saline 8 5 32.1±3.7 28.8± 3.3
Leuprolide 9 8 27.8± 1.0 28.7 ± 1.7
448 G. Casadesus et al. / Biochimica et Biophysica Acta 1762 (2006) 447452
Page 2
time (Baseline and 3 months) as a repeated measures factor. The Student's t test
was used to determine differences in amyloid-β burden between leuprolide
acetate and saline-treated animals.
3. Results
Leuprolide acetate treatment, in accord with previous data
[27,28], significantly lowered LH secretion in our model
(P b 0.02) (Fig. 1). Importantly, these declines led to sustained
cognitive ability as m easured by spontaneous alternation
behavior in the Y-maze task when compared to saline treatment
(F
1,11
=14.745, P b 0.01) (Fig . 2). Specifically, while both
groups were comparable at baseline (t
1,11
= 0.944, P b 0.35),
leuprolide acetate-treated animals showed significantly lower
rate of decline when compared to saline treated animals at 3
months post-treatment (t
1,11
= 29.438, P b 0.02). Importantly,
sustained performance was present in the absence of differences
in locomotor activity across groups (total number of arms
entered/5 min trial) (F
1,11
= 0.670, Pb 0.430).
A Student's t test statistical analysis used to determine
differences in amyloid-β deposition in treated and non-treated
groups revealed that leuprolide acetate treatment significantly
decreased the levels of amyloid-β deposition in the hippocampi
of treated versus non-treated aged animals (t
1,10
= 3.782,
P b 0.01) (Fig. 3). Notably, reductions in amyloid-β were
significantly correlated (Pearson's analysis) with improvements
in cognitive performance (r = 0.75, P b 0.05), such tha t
leuprolide acetate-mediated decreases in levels of amyloid-β
deposition were associated with improved performance in the
Y-maze task.
4. Discussion
Our data reveal that treatments that target HPG axis
hormones such as LH can modulate cognitive behavior in
aged AβPP transgenic mice, and also decrease the extensive
deposition of amyloid-β. These results support our hypothesis
that HPG axis function, and in particular the changes that occur
later in life (i.e., elevations in LH following menopause/age-
related declines in testosterone ), may play an important role in
the pathogenesis of AD [1,15,37,38].
Coupled with the decreases in LH, leuprolide acetate
treatment leads to decreases in sex steroids such as estrogen
which have been associated with declines in cognitive output
[3944]. Therefore, our data suggest that, at least in aged
AβPP transgenic mice, the positive effects of LH ablation
override any negative effects of estrogen depletion. Indeed, as
shown in this study, leuprolide acetate treatment maintains
alternation behavior in the Y-maze task, which has been
interpreted to reflect intact working memory. Alternation
behavior also depends on the animal's innate tendency/
preference to alternate, leading to the possibility that
treatment, rather than improving/sustaining memory, could
increase alternating preference. The fact that our data show
sustained rather than improved behavioral output in the
treated animals compared to controls and the fact that treated
animals did not show increases in overall arm entries nor any
directional biases, suggests that treatment did indeed sustain
short-term memory rather than potentiate their preference to
alternate. Such an assertion is in concert with data
demonstrating that the modulation estrogen in the AβPP/
PS-1 animal model of AD leads to improvements in cognitive
behavior but, and unlike our findings, no changes in
pathological features of AD [45]. This slight discrepancy in
results can be explained by a differential LH status in the
animals of the two studies since while in our study we ablated
both estrogen and LH concurrently, ovariectomy [45] leads to
declines in estrogen but a rise in the levels of LH and
administration of estrogen (c.f. HRT) does not decrease LH
levels beyond baseline. Therefore, one possibility is that it is
only the decrease in estrogen when it is coupled with an
increase in LH that leads to behavioral impairments and it is
only the ablation of LH that leads to changes in amyloid-β
pathology in these mice. Additionally, such differences could
Fig. 1. Serum mouse LH levels (mLH pg/ml± SEM) measured by RIA for saline
and leuprolide acetate-treated animals (n = 4/group). *Indicates significance at
P b 0.02.
Fig. 2. Y-Maze performance in Tg2576 mice after leuprolide acetate (n =8) or
saline treatment (n = 5) at baseline and after 3 months. Figure illustrates the mean
% alternations expressed as % change from baseline. * Indicates significance at
P b 0.05.
449G. Casadesus et al. / Biochimica et Biophysica Acta 1762 (2006) 447452
Page 3
also arise from the differences in techniques used (silver stain
vs. 4G8, a non-human specific antibody). Clearly, future, more
in depth, studies targeting all of these varia bles should be
carried out to clarify the interactive role of these hormones on
cognition and AD-related pathology. That withstanding, the
data do provide compelling evidence that LH is an important
component in the pathophysiological processes of AD.
The precise mechanistic pathway by which LH is involved in
AD is still under investigation, nonetheless, that LH modulates
the processing of Aβ PP [27] may be important given the
proposed centr al role of amyloid- β in AD pathogenesis [46] or
its proposed indirect role as a surrogate marker of neuronal
health [47,48]. In this regard, the reduction of amyloid-β and
coincident sustainment of alternation behavior following LH
ablation, observed in this study, is in agreement with previous
studies showing a correlation between amyloid-β burden and
cognition [49,50]. Importantly, given the high density of LH
receptors in the hippocampal region [23] and the higher levels
of LH in the brains of patients with AD [14,16] it is likely that
LH plays a significant role in the pathogenesis of the disease
dependent, as well as independent, of amyloid-β-related
processes.
Based on the aforementioned notion that LH is a driving
pathogenic force in AD, leuprolide acetate, a gonadotropin-
releasing hormone agonist, which suppresses LH to undetect-
able levels by down-regulating pituitary gonadotropin-releasing
hormone receptors [27,28], might be an effective method of
treatment for patients with AD. A previous study in humans
demonstrated that treatment with leuprolide acetate led to initial
increases in serum concentrations of amyloid-β 140 [51]; this
led to the assumption that declines in sex steroids by chemical
castration could lead to an increase in AD pathogenesis.
However, it is important to note that leuprolide acetate is a
gonadotropin-releasing hormone agonist which initially
increases the levels of LH before the levels decline and
therefore, an initial increase in LH could account for the initial
increases in serum amyloid-β observed. On the other hand,
increased serum amyloid-β may also reflect increased efflux of
amyloid-β from brain, as has been documented in transgenic
AβPP mice after immunotherapy [52].
Importantly, to reflect a realistic therapeutic window as it
would apply to human patients, in our study we used aged mice
where cognitive decline and amyloid deposition are both
evident. In addition, and without attempting direct comparisons
across species, studying aged rather than young female mice
provided a similar hormonal environment to that of a post-
menopausal female (i.e., deregulation and responsiveness to
gonadotropins as well as low estrogen levels), which is typically
the population that develops AD [53]. However, in order to
study the full spectrum of leuprolide acetate treatment effects,
future studies should include a young group as well as an
ovariectomized group. Certainly, the complex interaction
between all the HPG axis components suggests that it is
unlikely that any one hormone of this axis plays a single and
predominant role but rather it may be the balance or ratio of one
hormone to another, i.e., LH to estrogen or testosterone. In this
Fig. 3. Amyloid-β burden measured as % area stained in the entire hippocampus of 11 sections/brain/animal is significantly lower in animals treated with leuprolide
(n = 8) compared to saline-treated animals (n=5, *P b 0.05). Representative image of amyloid-β-burden in Tg2576 mice after saline (S) or leuprolide (L). Scale bar,
200 μm.
450 G. Casadesus et al. / Biochimica et Biophysica Acta 1762 (2006) 447452
Page 4
regard, individuals with higher LH to sex steroid ratios such as
women [54] and men [55] with lower endogenous sex steroid
levels (i.e., high LH to estrogen ratio) show higher rates of AD
and would likely benefit from leuprolide acetate treatment more
than women/men with higher endogenous levels of estrogen/
testosterone (lower LH:estrogen ratio), who have lower rates of
AD. Likewise, in men, treatment of leuprolide acetate could be
beneficial albeit masked by the effects of testosterone depletion
[56], in which case, testosterone replacement could be ideal.
Therefore, and considering that the totality of hormonal
influences cannot be ignored, our study demon strates that
targeting LH with leuprolide acetate, a product already safety-
approved for therapeutic use in prostate cancer, is as effective if
not more effective, as shown by its capacity to both positively
modulate cognition and reduce amyloid-β load, than estrogen
therapy alone. Likewise, the fact that leuprolide acetate was
capable of modulating cognitive behavior and reducing
advanced amyloid-β deposition in aged animals suggests that
this treatment may be an effective treatment strategy even at late
stages of disease. In this regard, a recently completed phase II
clinical trial (http://clinicaltrials.gov/ct/show/NCT00076440?
order=6) indicates that patients treated with high doses of
leuprolide acetate show a stabilization in cognitive decline
(ADAS-Cog, ADCS-CGIC) and activities of daily living
(ADCS-ADL) (http://www.secinfo.com/d14D5a.z6483.htm,
pp. 5664), therefore our findings are in agreement with
those in human trials.
Acknowledgements
We would like to thank Dr. Bob Switzer (Neuroscience
Associates Inc.) for his invaluable help with the tissue
preparation and amyloid-β staining and Dr. Nett (Endocrine
Laboratory at ARBL-Colorado State University) for his help
and expert input on serum LH measurements. Work in authors'
laboratories is supported by Voyager Pharmaceutical Corpora-
tion, the Alzheimer's Association (MAS), Philip Morris USA
Inc., and Philip Morris International (GC). Drs. Atwood, Perry
and Smith are consultants to Voyager and own equity.
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    • "An entry was scored when the four paws of the animals were completely in the arm of the Y-maze. The percentage alternation, which indicated memory performance, was calculated by dividing the total number of alternations by the total number of arm entries, minus two and multiplied by 100 [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: The effects of oral administration of low doses of monosodium glutamate (MSG) on behavioral phenotypes, biomarkers of oxidative stress in the brain and liver enzymes in mice were evaluated in this study. Mice were treated orally with MSG (100, 250 and 500 mg/kg) daily for 21 days before testing for behavioral phenotypes; memory, anxiety, spontaneous motor activity (SMA) and depression. Thereafter, the brain levels of malondialdehyde (MDA) and glutathione (GSH) as well as the activities of liver enzymes, aminotransferase (AST) and alanine aminotransferase (ALT) were determined spectrophotometrically. MSG did not produce significant (P > 0.05) impairment of memory in the Y-maze test. It also failed to modify the behaviors of mice in the elevated plus maze and light/dark transition tests of animal models of anxiety. MSG had no significant effect on SMA but produced depressive-like symptoms in the forced swim test at a dose of 500 mg/kg. Moreover, it increased the levels of MDA and decreased GSH concentrations in brain tissues of mice. The activity of AST and ALT were elevated in the blood of MSG-treated mice suggesting liver injury. Taken together, these findings suggested that MSG induced oxidative stress in the brain and impaired liver functions but did not produce any behavioral abnormalities in mice at lower doses.
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    • "Though there is no total consensus in research on different AD mouse models, most research supports a positive effect of leuprolide acetate on AD pathology. A female aged transgenic mouse model of Alzheimer's disease (Tg2576) showed decreased amyloid-β plaque deposition when treated with leuprolide acetate (Casadesus et al., 2006). Similar results were observed in tgArcSwe mice, in which leuprolide acetate led to a significant decrease in cortical but not hippocampal plaque load when compared to placebo controls (Nuruddin et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease is one of the most prevalent and costly neurological diseases in the world. Although decades of research have focused on understanding Alzheimer's disease pathology and progression, there is still a great lack of clinical treatments for those who suffer from it. One of the factors most commonly associated with the onset of Alzheimer's disease is a decrease in levels of gonadal hormones, such as estrogens and androgens. Despite the correlational and experimental data which support the role of these hormones in the etiology of Alzheimer's disease, clinical trials involving their reintroduction through hormone therapy have had varied results and these gonadal hormones often have accompanying health risks. More recently, investigation has turned towards other hormones in the hypothalamic-pituitary-gonadal axis that are disrupted by age-related decreases in gonadal hormones. Specifically, luteinizing hormone, which is increased with age in both men and women (in response to removal of negative feedback), has surfaced as a potentially powerful player in the risk and onset of Alzheimer's disease. Mounting evidence in basic research and epidemiological studies supports the role of elevated luteinizing hormone in exacerbating age-related cognitive decline in both males and females. This review summarizes the recent developments involving luteinizing hormone in increasing the cognitive deficits and molecular pathology characteristic of Alzheimer's disease. Copyright © 2015. Published by Elsevier Inc.
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    • "An entry was scored when the four paws of the animals were completely in the arm of the Y-maze. The percentage alternation, which gives a measure of working memory, was calculated by dividing the total number of alternations by the total number of arm entries, minus two and multiplied by 100 [21]. An alternation behavior was defined as consecutive entries into all three arms (i.e. "
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