Neuroscience Letters 463 (2009) 93–97

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Age-dependent changes in noradrenergic locus coeruleus system in

wild-type and APP23 transgenic mice
Patricia Szot a,1 , Debby Van Dam b,1 , Sylvia S. White a , Allyn Franklin a ,
Matthias Staufenbiel c , Peter Paul De Deyn b,d,∗
a
Northwest Network for Mental Illness Research, Education, and Clinical Center, Veterans Administration Puget Sound Health Care System,
and Department of Psychiatry and Behavioral Science, University of Washington, Seattle 98195, USA
b
Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp,
Universiteitsplein 1, B-2610 Wilrijk, Belgium
c
Novartis Institutes for Biomedical Research Basel, Basel, Switzerland
d
Department of Neurology – Memory Clinic, Middelheim General Hospital, ZNA, Lindendreef 1, B-2020 Antwerp, Belgium

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

Article history: Alzheimer’s disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific
Received 2 April 2009 regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several
Received in revised form 17 July 2009 animal models of AD have been developed that exhibit some of the pathophysiological changes in the
Accepted 17 July 2009
CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the
LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at
Keywords:
the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression.
APP23 transgenic
Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice,
Norepinephrine
Locus coeruleus
the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic
Tyrosine hydroxylase neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate
Aging an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the
Alzheimer’s disease amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no
difference between 6 and 12 months. These observations indicate that any study comparing the nora-
drenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested
and limit age differences between control and experimental groups to the absolute minimum. More
importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied
to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish
between potential therapeutic and strain-specific developmental or age-related alterations.
© 2009 Elsevier Ireland Ltd. All rights reserved.

Alzheimer’s disease (AD), a neurodegenerative disorder, is char-
acterized by cognitive impairment and the loss of neurons in
the cortex and hippocampus. The locus coeruleus (LC), the major
noradrenergic locus in the CNS, also demonstrates substan-
tial loss of neurons in AD [4,7,13,23,25,40,44]. Interestingly, the
surviving neurons in the LC demonstrate many compensatory
changes in response to the neuronal loss [1,10,11,16,19,24,28,29,
32–34,40,41,43,44]. Because the noradrenergic system has been
shown to play a major role in learning and memory [15], it is
∗ Corresponding author at: Laboratory of Neurochemistry and Behaviour, Institute
Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Univer-
siteitsplein 1, B-2610 Wilrijk, Belgium. Tel.: +32 3 820 26 20;
fax: +32 3 820 26 18.
E-mail addresses: peter.dedeyn@ua.ac.be, dedeyn@skynet.be (P.P. De Deyn).
1
Joint first authorship.
important to determine how noradrenergic neuronal loss with
compensatory changes affects memory.
Several different animal models of AD have been developed uti-
lizing the genetic information obtained from human AD studies
[12,50]. These various animal models represent a powerful tool
in describing time-linked pathophysiological mechanisms in the
CNS that are often not accessible in patients [50], and allow for the
development of drugs for treating these pathological changes asso-
ciated with dementia. The amyloid precursor protein 23 (APP23)
mouse harbors the Swedish double mutation, which is known to
cause early-onset familial AD in humans [8,26,36]. The neuron-
specific promoter and the integration of the human (APP) carrying
the Swedish double mutation into the mouse genome lead to a
seven-fold overexpression of the human APP (hAPP) compared to
the endogenous mRNA level. The first amyloid plaques appear in the
frontal cortex and the subiculum at the age of 6 months, to grow in
size and number with age to occupy the thalamus and amygdala by

0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2009.07.055
94 P. Szot et al. / Neuroscience Letters 463 (2009) 93–97
the age of 12 months and eventually large parts of the hippocam-
pus and neocortex at the age of 24 months [38]. APP23 mice display
high levels of face validity with regard to cognitive and behavioral
alterations [20,21,31,49,52,54–58], as well as predictive validity
[48,53]. Impairment of cholinergic transmission, the prominent
neurochemical deficit in Alzheimer brain, as indicated by decreased
specific acetylcholinesterase and choline acetyltransferase activity
levels was observed in basal forebrain nuclei of APP23 transgenic
mice [51,52]. Recently, Van Dam et al. [51] described changes in
norepinephrine (NE) concentration in specific regions of the APP23
transgenic mouse. In most brain regions analyzed, increased NE lev-
els compared to wild-type (WT) values were seen. These increased
NE levels reached significance in frontal cortex, mesencephalon and
medulla oblongata. These data suggest an alteration in the nora-
drenergic LC neurons. Therefore, the purpose of this study was to
determine if there is a loss of noradrenergic neurons in the LC of
APP23 transgenic mouse as compared to WT mice, or if the LC nora-
drenergic neurons have altered synthesis for NE. Because there is an
age-dependent deposition of amyloid plaques in the APP23 trans-
genic mouse, we measured tyrosine hydroxylase (TH) mRNA in the
LC of APP23 mice at various ages before and after the deposition of
plaques. TH is the rate-limiting enzyme in the synthesis of NE and
has been used to assess the loss of noradrenergic neurons in the LC
in AD subjects [40].
Transgenic APP23 mice were genetically engineered in a hybrid
C57BL/6 × DBA2 background by Sturchler-Pierrat et al. [38]. The
neuron-specific murine Thy-1.2 promoter drives human amyloid
precursor protein (APP) 751 cDNA harboring the Swedish dou-
ble mutation (K670N/M671L), associated with familial AD. Mice
were backcrossed to the C57BL/6J strain for at least 20 gen-
erations to obtain an isogenic line. Male heterozygous APP23
mice and WT control littermates were bred and aged within
the facilities of the Laboratory of Neurochemistry and Behaviour,
University of Antwerp. Genotypes were confirmed by PCR. Mice
were housed in mixed-genotype groups in standard mouse cages
(38.2 × 22 × 15 cm; length × width × height) with sawdust as bed-
ding material and under conventional laboratory conditions;
constant room temperature (22 ± 2 ◦ C), humidity level (55 ± 5%), a
12-h light:12-h dark cycle (lights on at 8 AM) and food (Carfil, Oud-
Turnhout, Belgium) and water available ad libitum. All experiments
were approved by the Animal Ethics Committee of the University
of Antwerp and performed in accordance with the European Com-
munities Council Directive (86/609/EEC).
Heterozygous APP23 mice and WT littermates were killed by
cervical dislocation at the age of 3 months (APP23 n = 8; WT n = 10),
6 months (APP23 n = 9; WT n = 8) or 12 months (APP23 n = 7; WT
n = 11). Brains were quickly removed, frozen on dry ice and stored at
−80 ◦ C until further manipulations. Serial coronal sections (18 ␮m)
through the LC were cut on a cryostat, thaw mounted onto Fisher
Superfrost slides, and stored at −70 ◦ C.
Tissue preparation and labeling of TH oligonucleotide probe
was performed as described previously [42]. The TH oligonu-
cleotide probe was a 48-base probe complementary to nucleotides
1351–1398 of the rat TH mRNA [17]. The oligonucleotide was
3 -end-labeled with [33 P]dATP (Perkin Elmer, Boston, MA) using
terminal deoxyribonculeotidyl transferase (Invitrogen, Piscataway,
NJ). The TH probe contained 0.93 × 106 cpm/50 ␮l and was washed
as described in detail in previously published work [42]. Slides
were coated with NTB Nuclear Track Emulsion (undiluted) (East-
man Kodak, Rochester, NY) and stored at −20 ◦ C for 4 days. Slides
were developed as described previously [42].
Quantification of TH mRNA in the LC expression was similar to
that performed by Szot et al. [40]. The number of cells that achieved
labeling three-fold higher than background was counted bilaterally
over 5 consecutive sections for each animal and totaled as TH-
positively labeled cell ± SEM. The 5 sections encompass ∼80% of
the LC that exhibit TH-positively labeled neurons. The density of
TH mRNA expression per neuron was performed measuring silver
grains over the cell bodies of labeled neurons that were three-
fold higher than background under 20× dark-field illumination
using the MicroComputer Imaging Device system (MCID) (Imag-
ing Research, St. Catherines, Ontario, Canada). Therefore, all labeled
neurons that were counted as positively labeled were also quanti-
fied for the amount of TH mRNA expression per neuron. The data
are expressed as the average of grains/neuron ± SEM bilaterally over
the 5 consecutive sections for each animal.
Two-way analysis of variance with correction for repeated
measures (2-way RM-ANOVA) was used to evaluate significant dif-
ferences between mean number of TH-positively labeled neurons
and the amount of TH grains/neuron. Genotype and age were con-
sidered as possible sources of variation. In case of a significant
P-value, a post hoc Tukey multiple comparison tests were run. Sta-
tistical analyses were performed using Sigmastat software (SPSS
Inc., Erkrath, Germany) with the level of probability set at 95%.
The number of TH-positively labeled neurons was summed over
5 consecutive sections (bilaterally) through the LC (Fig. 1A). The
amount of TH mRNA expressed per positively labeled neuron was
averaged over the 5 consecutive sections (bilateral) (Fig. 1B). Two-
way RM-ANOVA failed to show a significant effect of genotype on
both parameters (P = 0.343 and P = 0.566, respectively). However, a
significant effect of age, irrespective of genotype, was observed for
both the number of TH-positive neurons (F2,47 = 16.901, P < 0.001)
and the amount of TH grains/neuron (F2,47 = 12.977, P < 0.001).
No significant effect of the interaction genotype × age was noted
(P = 0.788 and P = 0.320, respectively). Post hoc Tukey multiple
comparisons indicated a significant increase in the number of TH-
positive neurons and the amount of TH grains/neuron expressed
in LC between the age of 3 months and 6 months (P < 0.001; for
both parameters) and 3 months and 12 months (P < 0.001; for both
parameters) in both WT and APP mice, but not between 6 months
and 12 months (P = 0.289 and P = 0.904). Dark-field images of TH
mRNA labeling in the LC are shown at midlevel of the LC in 3, 6 and
12-month-old WT mice (Fig. 1C).
The APP23 mouse does not exhibit a loss of noradrenergic neu-
rons in the LC at any age studied or a change in the expression of
TH in each neuron, despite a previous study suggesting alterations
in the noradrenergic transmission system of APP23 mice aged 7–8
months [51]. It should be kept in mind, however, that this previ-
ous study used HPLC analysis of NE levels, which was not able to
distinguish between interstitial and intracellular neurotransmitter
levels. In addition, we should state that the presumed compen-
satory activation of noradrenergic neurons was not substantiated by
the analysis of 3-methoxy-4-hydroxyphenylglycol (MHPG). Since
MHPG is the predominant metabolite of NE, an increase of the
MHPG: NE ratio would suggest activation of the noradrenergic sys-
tem. The lack of TH mRNA alterations in light of the previously
published alteration in NE concentrations in APP23 brain could also
be attributed to a variety of other mechanism, including TH protein
stability, NE re-uptake into the terminal and NE uptake into the
vesicle. Also, several of the regions where an increase in NE tissue
content was measured previously [51], receive only partial LC inner-
vation. APP23 mice are considered a valid animal model of AD; they
display an age-dependent deposition of plaques in the cortex, tha-
lamus, amygdala and hippocampus [38], cognitive and behavioral
impairment [20,21,31,49,52,54–58] and neuronal loss [5,6]. How-
ever, this study indicates there is no loss of noradrenergic neurons
in the LC of APP23 transgenic mice, even at an age when plaques
are present [38].
The link between LC degeneration and AD was previously shown
by Heneka et al. [18] in the APP23 model. Neurotoxic lesioning of the
LC augmented amyloid burden paralleled with increased inflam-
matory reactions, as well as increased memory deficits, reduced
 P. Szot et al. / Neuroscience Letters 463 (2009) 93–97 95

Fig. 1. Quantification of tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus (LC) of APP23 mice at 3, 6, and 12 months. (A) Represents the mean summed
number of TH-positively labeled neurons over five consecutive slices through the LC of 3, 6 and 12-month-old APP23 mice (black bars) and wild-type (WT) control littermates
(white bars). (B) Represents the average expression of TH grains/neuron in the same set of mice. (C) Dark-field images of TH mRNA labeling in the LC of 3, 6, and 12-month-old
WT mice. Asterisks indicate a significant effect of age with respect to 3-month-old mice irrespective of genotype by post hoc Tukey multiple comparison: ***P < 0.001. Scale
bar = 100 ␮m.

cerebral glucose metabolism, disturbed neuronal integrity and
attenuated acetylcholinesterase activity. The integrity of the LC in
aged hemizygous PDAPP mice (age 23 months) showed no loss of
TH-positive neurons in the LC, but 24-month-old homozygous mice
exhibited neuronal shrinkage in the portion of the LC with neu-
rons projecting to the cortex and hippocampus [14]. However, aged
(16–23 months) double transgenic mice expressing mutated forms
of both human APP and presenilin 1 (APP/PS1) showed a reduc-
tion of 24% to 50% in the total number of TH-positive neurons in
the LC compared to age-matched WT mice using immunohisto-
chemistry [22,27]. Degeneration of noradrenergic neurons in the
LC of APP/PS1 mouse occurs after the deposition of A␤ and loss
of noradrenergic terminals in forebrain regions [22]. In addition,
the APP/PS1 mice were previously shown to exhibit significantly
reduced hippocampal NE levels at the age of 12 and 18 months
(30% and 40%, respectively), whereas no changes were noted in
frontal cortex and brainstem [39]. So it appears the presence of both
mutation in the APP and PS1 gene are required to observe a loss of
noradrenergic neurons. However, these studies did not determine
if there is compensation in the expression of TH in the surviving
neurons, as observed in AD subjects [40].
The present study clearly indicates an important increase of
the LC-NE system after 3 months in C57BL/6 mice, which seems
independent of genotype in this case. Both the number of TH-
positive cells and the number of TH-positive grains/cell significantly
increased between the age of 3 and 6 months with no change in
noradrenergic markers between 6 months and 12 months. To our
knowledge, this is the first study describing such age-dependent
changes in LC of mice, and of C57BL/6 in particular. Several stud-
ies have shown changes in the number of TH-positive LC neurons
and/or LC volume in rat brain around postnatal day 14 [2,30,35].
Concerning LC-related changes with further aging, some contra-
dictory observations have been published; both increased [37] and
unaltered [9,46,47] TH mRNA levels have been described in aging
rat LC. Much less information, however, is available for postnatal LC
development and TH levels, as well as further age-related changes
in mouse brain [45]. Noradrenergic neurons of the LC maintain their
capacity to adapt and respond to, e.g. injury well into adulthood, as
exemplified in lesion studies. Several reports have indicated the
presence of transient or “sleeping” neurons in which TH expression
is inactivated or at a low level of activation [2,3]. Our observations
indicate that both activation of transient cells, as well as increased
activation of TH-positive neurons can be presumed.
These observations indicate that any study comparing the nora-
drenergic system between WT (C57Bl/6) and experimental mice
(e.g., lesion model, transgenic model) should strictly choose the
age to be tested and limit age differences between control and
experimental groups to the absolute minimum. More importantly,
when chronic therapeutic interventions targeting the noradrener-
gic system are applied to a mouse model, and related parameters are
studied longitudinally, care should be taken to distinguish between
potential therapeutic and strain-specific developmental or age-
related alterations.
Acknowledgements
This work was supported by the Fund for Scientific Research-
Flanders (FWO grant G.0164.09), Interuniversity Poles of Attraction
(IAP Network P6/43), Methusalem Financing, Stichting Alzheimer
Onderzoek/Fondation pour la Recherche sur la Maladie Alzheimer
(SAO/FRMA), agreement between Institute Born-Bunge and the
University of Antwerp, the Medical Research Foundation Antwerp,
96 P. Szot et al. / Neuroscience Letters 463 (2009) 93–97
Neurosearch Antwerp, the Thomas Riellaerts Research Fund and
Mental Illness Research, Education, Clinical Center, Veterans
Administration Puget Sound Health Care System (PS). D.V.D. is a
Postdoctoral Fellow of the FWO.
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