Neuroscience Letters 650 (2017) 146–152

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

Research article

Sleep deprivation accelerates the progression of alzheimer’s disease

by influencing A␤-related metabolism
Lihong Chen, Junshan Huang ∗ , Lanfang Yang, Xue-Ai Zeng, Ya Zhang, Xiufeng Wang,
Mingqi Chen, Xing Li, Yifan Zhang, Min Zhang
Fujian Institute of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fujian, 350003, China

h i g h l i g h t s

• Acute sleep deprivation elevates the levels of BACE1 in adult rats.

• Acute sleep deprivation affects little on A␤degradation.
• Acute sleep deprivation increases the secretion of A␤ in a time-dependent manner.

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

Article history: Sleep disorders have previously been connected with the neurodegenerative pathology of Alzheimer’s
Received 16 February 2017 disease (AD) due to the aggregation of ␤-amyloid(A␤)peptides and tau proteinsinduced by sleep depri-
Received in revised form 11 April 2017 vation (SD). However, the underlying mechanisms remain unclear. Therefore, this study was performed
Accepted 24 April 2017
to clarify how A␤-related metabolism is regulated after SD. Three-month-old Sprague-Dawley rats
Available online 25 April 2017
(250–300 g) were randomly divided into 5 groups: two SD groups(i.e.,SD-2d and SD-4d), two platform
control groups(i.e.,PC-2d and PC-4d) and a home cage control group (CC). For the two SD groups, the-
Keywords:
modified multiple platform method (MMPM) was used to induce SD.Our experiments confirmed that SD
Sleep
Sleep deprivation
impaired cognitive function and increased the levels of A␤ peptides, a hallmark of AD. Additionally, we
Alzheimer’s disease found that SD significantly increasedthe levels of the ␤-site amyloid precursor protein (APP)-cleaving
␤-amyloid peptide(A␤) enzyme 1(BACE1, ␤-secretase), but had little impacton the levels of A␤-degradationenzymes.This result-
may be the main cause of the over-expression of A␤1-42 and A␤1-40. Our results suggested that SD
accelerates the progression of AD bymodulating A␤-related metabolism. This findinghasimportant impli-
cations for the diagnosis and prevention of AD.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction the formation of amyloid deposits and senile plaques, a hallmark of

Alzheimer’s disease(AD) is a common age-related progressive
neurodegenerative disease characterized by the aggregation and
accumulation of ␤-amyloid(A␤) peptides and hyperphosphory-
lated tau proteins [1]. The A␤ peptide is a fragment produced
by sequential cleavage of the amyloid precursor protein(APP) by
␤-secretase and ␥-secretase. This sequence of events is called
the ␤-amyloid cascade.␤-site APP-cleaving enzyme1(BACE1) is
responsible for the activity of ␤-secretase and plays a central role
in APP proteolysis.Excessive aggregation of A␤ ultimately leads to
∗ Corresponding author at: 282 Wusi Road, the Institute of Medicine Sleep
Research Center of Fujian, zip code 350003, China.
E-mail address: hjsh0908@163.com (J. Huang).
AD, and results in neurotoxicity and impaired cognitive and mem-
ory function.Therefore, reduction of A␤ peptide levels would slow
or delay the onset of AD in current animal models [2].
In addition,APP can also be cleaved by ␣-secretase and ␥-
secretase with no A␤ generation. Commonly, APP is degraded
through a non-amyloid pathway.Metalloprotease10 (ADAM10)
serves as a pivotal protector ␣-secretase by cutting APP in the
non-amyloidogenic pathway [3]. Previous studies have shown that
excessive ADAM10 expression increases the secretion of sAPP␣, a
neuroprotective fragment, and decreases the production of toxic
A␤ [4].
Neprilysin (NEP) and insulin-degrading enzyme(IDE) are two
important degradation enzymes that break down A␤ peptides [5].
A large body of literature has shown that over-expression of NEP
or IDE in the brain of AD animals significantly decreases the pro-

http://dx.doi.org/10.1016/j.neulet.2017.04.047
0304-3940/© 2017 Elsevier B.V. All rights reserved.
 L. Chen et al. / Neuroscience Letters 650 (2017) 146–152
duction of soluble A␤ and prevents amyloid plaque formation.
Increased production of A␤ peptides,combined with insufficient
degradation, resulted in A␤ accumulation.
Sleep problems are the most common condition observed
in medical practice. Survey results indicated that approximately
38.2% of the general population in China experience symptoms of
insomnia, whereas a lower incidence of 30% is found in Amer-
ica [6,7]. Sleep disorders lead to several adverse effects such as
impaired attention and memory, daytime sleepiness, fatigue, noc-
turnal awakenings, changes in mood, and even neurodegenerative
disease [8–10]. Among these complications, the most intriguing
topic is the relationship between sleep problems and AD.
Survey results indicated that up to 45% of patients with AD
exhibit disrupted circadian rhythms and fragmented sleep [11].
The duration of rapid eye movement(REM) sleep bouts is decreased
in AD patients compared with age-matched controls [12]. Recent
results from human and transgenic animal studies have shown that
amyloid deposition and tau aggregation can directly drive sleep
impairment [13,14]. Sleep problems also tend to occur in the early
stages of the disease. Based on this information, we hypothesize
that a bidirectional relationship exists between AD and sleep qual-
ity. Although accumulating evidence has demonstrated that sleep
loss may accelerate the progress of AD [15–17], the underlying
mechanisms remain unclear. In this study, we examined the alter-
ations of key enzymes in A␤ metabolism to testify our hypothesis.
2. Materials and methods
2.1. Animals
Experiments were carried out on forty 3-month-old male
Sprague-Dawley rats (250–300 g)purchased from Fujian Medical
University (Fujian, China). All animal investigations were complied
with the ARRIVE guidelines and performed in accordance with the
U.K.Animals(Scientific Procedures)Act. All experimental protocols
were approved by the Animal Ethics Committee of Fujian Insti-
tute of Chinese Medicine. Because increasing evidence supports the
hypothesis that the production of A␤ peptides in the brain is closely
connected to the sleep-wake cycle [18], we standardized the sam-
pling time across the rats to minimize difference caused by the
sleep-wake cycles.
2.2. Chemicals and reagents
The corticosterone ELISA kits (ab108821) were purchased from
Abcam (Cambridge, USA), and the A␤1–42 and A␤1–40 ELISA
kits were purchased from Invitrogen (Carlsbad, CA, USA). The
RT-PCR kits were purchased from Promega (Madison, WI, USA).
Primary antibodies, including the polyclonal rabbit anti-APP anti-
body #2452, monoclonal rabbit anti-BACE1 antibody#5606, and
monoclonal rabbit anti-␤-actin antibody #4970 were purchased
from Cell Signaling Technology(Boston,USA). The monoclonal rab-
bit anti-a disintegrin and ADAM10 antibodies(EPR5622) were
purchased from Abacm(Cambridge, USA). The rabbit anti-APP,c-
terminal antibody (SAB1403560) was from SIGMA (Sigma, St. Louis,
MO, USA).
2.3. Sleep deprivation procedure
The rats were randomly seperated into 5 groups (n = 8 per
group), including one cage control group(CC), in which rats were
maintained in their normal cages without sleep deprivation (SD);
two platform control (PC) groups(i.e.,PC-2d and PC-4d), in which
rats were kept on a wide platform for 2 days and 4 days, respec-
tively, without SD; and two paradoxical SD groups(i.e.,SD-2d and
147
SD-4d), in which rats were kept on small platforms for 2 days and
4 days, respectively.
The rats were housed in a temperature-controlled (22 ± 2 ◦ C)
room with a 12 h:12 h light–dark cycle (lights on at 07:00 a.m.).
We chose the modified multiple platform method (MMPM, a widely
accepted paradoxical SD model) to induce acute SD in this study.
Each SD rat was placed on a narrow platform in a water tank
(153*52*52 cm) containing 10 circular platforms (6.5 cm in diam-
eter) to ensure the rats could lie down on the platforms. The tank
was filled with water to a depth of approximately 1 cm below the
platforms. The rats were allowed to freely move around inside the
tank by jumping from one platform to another. When they reached
the paradoxical phase of sleep, they fell into the water and woke
up due to muscle atonia. To test the potential influence of environ-
mental stress, we also used a wide platform (15 cm in diameter),
which allowed the rats to sleep without falling into the water. The
rats had free access to chow pellets and water bottles on the top of
the tank. The water in the tank was changed daily throughout the
SD period. The CC group was kept in their normal cages.
2.4. Morris water maze
The Morris water maze(MWM) test, which includes a spatial
exploration test and a place navigation test, was performed in a
circular pool (160 cm in diameter and 55 cm in depth) with an
invisible platform (12 cm in diameter and 25 cm in depth). The
water in the pool was mixed with milky SiO2 powder. The plat-
form was located in the middle of the first quadrant, 1 cm below
the water surface. A video camera recorded the animals, and the
time it took for each animal to climb onto the platform. The data
were analyzed using software purchased from Chinese Academy
of Medical Sciences. During a trial, a rat was placed into the water
from one of the start positions, facing the wall. Learning trials were
conducted over 5 days, with 4 trials per day. If the animal reached
the platform, the timer was stopped. If the animal failed to find the
platform within 90 s, the animal was placed on the platform for 10 s
to help it learn the platform’s location. On day 6, we removed the
platform,released the rat from the third quadrant(180◦ from the
original platform position), and recorded the amount of time the
rat spent in each quadrant and the number of times it crossed the
region in which the platform was previously located over a 90-s
period. The data were used to assess memory retention. All steps
listed above were in accordance with a previously described pro-
tocol for MWM [19]. After testing, the rats were dried with a towel
to keep them warm. During the experiment, the temperature of
the water remained within 19–22 ◦ C, and all landmarks around the
maze remained the same.
2.5. Tissue collection
At the end of the experiment, all of the rats were anesthetized
with an intraperitoneal injection of 2.5% sodium pentobarbital
(2 ml/kg). The brains were harvested after the blood was collected
by intracardiac perfusion ofice-cold phosphate-buffered saline (pH
7.4)through the left ventricle and simultaneous exsanguination
through the right atrium. The left cerebral cortex of each brain was
dissected on ice and immediately stored at −80 ◦ C for western blot-
ting. The entire right cerebral cortex were then dissected from the
brain and stored in RNA later at−20 ◦ C for RT-PCR. Plasma was sep-
arated from the blood by centrifugation at 4 ◦ C and then stored at
−80 ◦ C for future assessment of corticosterone concentrations (see
below).
148 L. Chen et al. / Neuroscience Letters 650 (2017) 146–152

2.6. Measurement of plasma corticosterone and brain Aˇ by ELISA

Portions of the left cerebral cortex were weighed and

homogenized with TBS containing 1% protease inhibitor cocktail
(Sigma-Aldrich, St. Louis, MO).Then, the brain homogenates were
centrifuged at 16,000 rpm for 20 min at 4 ◦ C, and the supernatants
were used to measure A␤1-42 and A␤1-40 levels using ELISA kits
in accordance with the manufacturer’s protocol. Plasma corticos-
terone levels were measured with an ELISA kit (ab108821;Abcam).
The best density wasread at 450 nm, and the corticosterone con-
centrationineach samplewas determined using a standard curve.

2.7. Western blot

The frozen cortical tissues were homogenized on ice, and

the protein concentration was measured with BCA Protein Assay
Kits(P0012,Beyotime(Beijing,China)). Briefly, the proteins obtained
from the cortical tissues were separated by electrophoresis
using 10% gels and transferred to a polyvinylidene fluoride
(PVDF)membrane(Sigma–Aldrich, San Louis, MO, USA). To study
the influence of sleep on the ␤-amyloid pathway, the blots were
Fig. 1. Sleep deprivation evokes an impaired capacity of learning and memory. The
latency time to reach the hidden platform decreased over time and sleep deprivation
rats showed an increased escape latency to find the platform compared with control
groups at the same time point(p < 0.05). Results are shown as means ± S.D. n = 8.

incubated with the appropriate antibodies using the ECL-PLUS sys-

tem. ␤-actin was used as the internal standard. All images were 3. Results
analyzed using AlphaView SA software (Protein Simple, version
3.4.0.0). 3.1. Plasma corticosterone levels

The plasma corticosterone levels did not differ among the CC,
PC and SD groups (Table 1).
2.8. RT-PCR

Briefly, total RNA was extracted from the homogenized corti-
caltissues with Trizol reagent (Madison, WI, USA). Then, RT-PCR
assays were performed as described in the manufacturer’s proto-
col. Primer Premier 5.0 software was used to choose primers and
probes for our genes of interest (ADAM10,BACE1,NEP and IDE), and
the data were analyzed using a LightCycler 480system(Roche). A
AMV First Strand cDNA Synthesis Kit (SK2445) was used to prepare
cDNA from each RNA sample. The cDNA amplification was carried
out as follows: denaturation at 95 ◦ C for 3 min, followed by 45 cycles
of denaturation at 95 ◦ C for 7 s, primer annealing at 57 ◦ C for 10 s,
and extension at 72 ◦ C for 15 s. All assays were performed in tripli-
cate, and ␤-actin served as a housekeeping gene to compare mRNA
expression levels.
2.9. Statistical analysis
The data were analyzed using SPSS 19.0 software and shown
as the mean ± standard deviation. The MWM data were analyzed
using a general linear model,ANOVA analyses followed by LSD post
hoc test were used for multiple comparisons. The result shown was
a representative of three independent experiments. Differences
were considered significant at p < 0.05.
3.2. Sleep deprivation elevated Aˇ1-42 and
Aˇ1-40concentrations
As shown in Table 1, A␤ 1-42 and A␤1-40 levels after SD in
both the SD-2d and SD-4d rats were significantly elevated com-
pared to those in the PC-2d group and the PC-4d group, respectively.
Four days of SD significantly increased the level of A␤1-42 by 3.1
folds(p < 0.001)and of A␤1-40 by 1.9 folds (p < 0.001)compared to
those in the PC-4d group. Moreover, compared to the PC-2d group,
the SD-2d rats also displayed a 1.8-fold increase in A␤1-42 and a
1.3-fold increase in the level of A␤1-40 (p < 0.001). In contrast, no
differences were detected between the PC groups and the CC group.
The ratio of A␤1-42/A␤1-40 was significantly greater in the SD rats
compared to the PC groups. These results are consistent with pre-
vious findings [20] and indicate that sleep loss may increase the
secretion of A␤1-42 and A␤1-40.
3.3. Effect of sleep deprivation on cognitive function
The MWM test was used to assess learning and memory abil-
ities after rats were exposed to SD. The test is mainly divided
into two parts: a spatial exploration test and a place navigation
test. As shown in Fig. 1, over the 5-day trial periods, the perfor-
mance of all rats improved, as measured by the escape latency(the

Table 1
Plasma corticosterone (ng/ml, mean ± S.D.) and hippocampal A␤1–42 andA␤1–40 levels (pg/ml)after sleep deprivation. n = 6 for corticosterone and 8 for others.

A␤1-42 level(pg/ml) A␤1-40 level(pg/ml) A␤1-42/1-40ratio Plasma corticosterone(ng/ml)

CC group 109.92 ± 8.28 175.21 ± 6.90 0.63 ± 0.05 276.92 ± 17.82

PC-2d 118.05 ± 5.70 171.59 ± 5.41 0.69 ± 0.05 271.27 ± 27.74
PC-4d 110.30 ± 7.21 171.34 ± 7.02 0.64 ± 0.05 257.41 ± 12.55
SD-2d 207.41 ± 8.25a 219.64 ± 5.99a 0.95 ± 0.06a 278.42 ± 17.78
SD-4d 345.68 ± 8.60b 321.61 ± 6.07b 1.08 ± 0.04b 284.31 ± 19
a
PC-2d vs SD-2d, P<0.001.
b
PC-4d vs SD-4d, P<0.001.
 L. Chen et al. / Neuroscience Letters 650 (2017) 146–152
Fig. 2. To test for memory impairment (working memory retention), both groups of rat were tested for the percentage time spent in the quadrant platform (a) and the times
of rats crossing the target platform (b). Significant difference was found between SD groups and control groups,while no differences were detected between the PC groups
and the CC group, *p < 0.05 **p < 0.01 ***p < 0.001.
Fig. 3. The results of representative western blot(WB) for each proteins.
average time to find the submerged platform). The data were pre-
sented as means ± S.E. and analyzed by repeated-measure two-way
(group × day) ANOVA. The escape latency continually decreased
during the training phase. However, following SD, the performance
of the SD rats was significantly worse than that of the PC rats at
the same time points (p < 0.05). The escape latencies of the sleep-
restricted animals were significantly longer than those of the PC
rats. Probe trials conducted on day 6 demonstrated that after SD,
the sleep-restricted rats spent less time in the target quadrant (the
quadrant where the platform was located during training(p < 0.001,
Fig. 2a)), indicating their ability to find the platform was decreased
compared to that of the PC rats. Furthermore, the average number
of times the animals crossed the platform was significantly lower in
the SD-4d group compared to that of all the other groups (p < 0.001,
Fig. 2b). Overall, these results suggested that SD impairs learning
and memory in a time-dependent manner.
3.4. Sleep deprivation influenced the levels of enzymes involved
in APP processing
Fig. 3 shows a representative western blot(WB) for each pro-
tein. As shown in Fig. 4a, the APP/␤-actin optical density(OD) ratio
did not significantly differ among the 5 groups(F(4,25) = 1.354,
p = 0.278). This finding indicateed that SD has little influence on the
levels of APP. Next, we examined the expression of sAPP␤,ADAM10
149
and BACE1 to further analyze the correlation between sleep and the
␤-amyloid cascade.
Both ␣-secretase and ␤-secretase are crucial components in
the amyloid pathway. A significant decrease in ␣-secretase activ-
ity in patients with moderate-to-severe AD was recently reported
[21,22]. As shown in Figs. 5a and 4c , RT-PCR and WB analysis
revealed that after 2 days of SD, the levels of ADAM10 mRNA and
protein were significantly elevated compared with those in PC-2d
rats(F(4,25) = 8.954, p < 0.001; p < 0.001 by LSD post hoc test),while
no differences in these levels were detected between the PC groups
and the CC group (p > 0.05). The RT-PCR results showed that com-
pared with that in the control group, the expression of ADAM10 was
higher in the SD-2d rats(1.19 ± 0.18). However, ADAM10 expres-
sion in the SD-4d rats(0.99 ± 0.12) did not differ from that in
the controls(p > 0.05). We next examined BACE1 protein expres-
sion levels. Compared with that in the PC-2d group, the ratio
in the SD-2d rats(1.18 ± 0.08)was increased(PC-2d 0.72 ± 0.09;
F(4,25) = 64.162, p < 0.001; p < 0.001 by LSD post hoc test). An even
greater increase was observed in the SD-4d rats(1.41 ± 0.10) com-
pared to the PC-4d rats (PC-4d 0.75 ± 0.11; p < 0.001). This tendency
was consistent with the RT-PCR results (Fig. 5b).
The sAPP␤/␤-actin OD ratio in the SD-2d group was signifi-
cantly elevated compared to that in the PC-2d group(0.55 ± 0.07
and 0.29 ± 0.06, respectively, F(4,25) = 63.330, p < 0.001; p < 0.001
by LSD post hoc test). Moreover, the amount of sAPP␤ in the SD-
4d group(0.65 ± 0.06) was further increased over that in the SD-2d
group (p < 0.001).
3.5. NEP and IDE
Neprilysin (NEP) and insulin-degrading enzyme(IDE) are two
important degradation enzymes that break down A␤. Some stud-
ies have revealed that the activity of NEP decreases during normal
aging and in the early stage of AD [23,24]. A strong negative correla-
tion between the level of NEP and the level of A␤ and the formation
of amyloid plaque deposits has also been reported [25]. However, in
our research, the levels of NEP did not significantly differ between
the 5 groups (Fig. 5c; F(4,25) = 0.685, p = 0.609).
IDE mainly degrades soluble A␤ monomers [26,27]. Some sur-
veys have suggested that the level and activity of IDE continually
decreases during the progression from mild cognitive impairment
to AD. Fig. 5d demonstrated that the SD rats had a lower amount
150 L. Chen et al. / Neuroscience Letters 650 (2017) 146–152
Fig. 4. The effect of sleep deprivation on the levels of APP ratio, sAPP␤ ratio, ADAM10 ratio and BACE1 ratio of rat brain cortex tissues, normalized on ␤-actin level. Data was
expressed as mean ± S.D. n = 6. *p < 0.05,** p < 0.01, ***p < 0.001 compared with the PC group respectively.
of IDE mRNA than the PC rats. However, the difference was not
statistically significant(F(4,25) = 1.174, p = 0.346).
4. Discussion
Recently, the bidirectional relationship between sleep disorders
and the neuropathology of AD has been the subject of numerous
investigations. A large body of evidence supports the association
between disrupted sleep and AD [28]. According to Wu’s findings
using drosophila models,changes in neuronal excitability underlie
the effects of sleep loss on AD pathogenesis [29]. Besides, A␤ accu-
mulation also seems to be dependent on neuronal activity [30]. The
strongest evidence for this connection is that the brain releases
more A␤ when neuronal firing is increased (during wakefulness)
[30,31]. Since sleep can downscale synaptic strength following the
synaptic potentiation that occurs during wakefulness,loss of sleep
may lead to neuronal hyperexcitation [32]. As a result, there will
be less overall neuronal activity and less release of A␤ into the
brain interstitial fluid [20]. The sleep-wake cycle of A␤ release,
i.e., increased during daytime and decreased during nighttime,
has been observed in both humans and mice [33]. Additionally, it
is clear that long wakefulness may contribute to the increase in
A␤ and development of amyloid plaques. Ooms et al. [34] found
that levels of A␤1-42 were elevated after a total night of SD in
healthy males. In addition, sleep can alleviate the AD-related neu-
ropathological process [35]. Unfragmented sleep could attenuate
age-related cognitive decline and A␤ peptide aggregation, leading
to the reduction of AD incidence.
The major finding of the present study is that acute SD induces
memory impairment and increases BACE1 expression and APP pro-
cessing. Although several studies [36,37] have previously shown
that SD may accelerate ␤-amyloid accumulation, most of these
studies used AD transgenic animals such as the 3xTgAD or 2xTgAD
mouse models,drosophila models or old rats in their experiments.
However, these rats have some limitations in the sleep research
field. Since old mice are more prone to A␤ accumulation compared
to adult mice [38],using the old rat model in our experiments could
have interfered with the effects of SD on A␤. Therefore, we chose
to use adult male Sprague-Dawley rats (3 months old; 250–300 g)
in our experiment to imitate healthy adult males and to reflect a
more cautious approach regarding the experiment’s translational
applicability.
The MMPM is a widely accepted method to induce SD, espe-
cially of REM sleep, in the sleep field. This method was used to
minimize the confounding effects of stress associated with a sin-
gle platform such as movement restriction. In addition, all of the
animals were raised together and were allowed to habituate to the
tank for 3 days. These procedures established a socially stable group
and eliminated other potential stress variables [39]. In our study,
plasma corticosterone levels, which were used as an indicator of
hypothalamic–pituitary-adrenal (HPA) axis activity, did not signif-
icantly differ between the 5 groups. Consistent with our findings,
Joukar et al. [40] reported the absence of a significant change in
plasma corticosterone levels after SD using the same method. One
possible reason accounting for this phenomenon is that the levels of
corticosterone decreased to the baseline due to the recovery during
SWS (SWS was relatively preserved during the experiment). Turek
et al. found that sleep deprivation resulted in the increase of corti-
costerone,while this increase did not persist long, it returned to the
baseline values after 4 h of recovery[41]. Accordingly, the increase
in BACE1 can be attributed to SD rather than to stress effects, which
are reflected by HPA axis hyperactivity. However, in this experi-
 L. Chen et al. / Neuroscience Letters 650 (2017) 146–152
Fig. 5. The bar graph shows the mRNA expression fold over the expression of the CC group. The levels of actin served as internal controls. Data was expressed as mean ± S.D.
n = 6. ***p < 0.001.
ment, we did not assess other stress effector systems such as the
adrenomedullary hormonal system, the vasopressin system or the
renin–angiotensin–aldosterone system.
In our experiment,we found that after 4 days of SD, the amount
of APP did not significantly differ from control levels. The ADAM10
levels were elevated in the SD-2d rats, but did not differ between
control and SD-4d rats. This result may be attributed to acute com-
pensatory mechanisms in the brain that act to maintain stable A␤
levels and decompensation after 4 days of sleep disruption.
BACE1 is the key enzyme for A␤ accumulation and is consid-
ered a therapeutic drug target in AD [42]. Our results showed
that BACE1 secretions in the SD rats continually increased com-
pared to control rats. We also found elevated ␤-secretase-derived
sAPP␤ fragments and increased A␤ production without APP alter-
ation. Several authors have reported that BACE1 levels and activity
increased in AD rats, suggesting that BACE1 elevation may play a
central role in the pathology of AD [43]. In addition, we further
investigated A␤ degradation. We found that after acute SD, NEP and
IDE levels were negligibly altered. SD,especially a short period of
acute SD, had little influence on levels of the degradation enzymes.
Accordingly, the elevation of A␤ peptide levels after SD was pri-
marily mediated by BACE1 rather than insufficient degradation.
5. Conclusion
Our data demonstrated that acute SD can accelerate the secre-
tion of A␤ peptides by elevating levels of BACE1 rather than by
slowing degradation in adult rats. Since an increasing amount of
data has shown a bidirectional relationship between sleep and AD,
151
we should take sleep disorders more seriously and treat them more
aggressively. Changes in sleep commonly seem to precede other
symptoms of AD; therefore, we can consider sleep disorders as a
potential indicator of AD. Additionally, BACE1 inhibitors are com-
monly used for AD therapy. To prevent A␤ over-production and
reverse the progression of AD, we should consider the prophylactic
use of BACE1 inhibitors or other anti-AD medications in insomnia
and other sleep disorders. Improving sleep quality may also be a
good way to prevent AD.
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