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NEUROPHARMACOLOGY
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences (H.O., A.N., K.M., T.Y., Y.O.), Division of Pharmacotherapy, Graduate School of Pharmaceutical Sciences (A.N., D.S., N.T., T.Y.), Department of Neurological Science, Graduate School of Medicine (R.-W.S.), and Research Center of Supercritical Fluid Technology, Graduate School of Engineering (Y.O.), Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan; Molecular Medical Science Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (K.O.); Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan (A.Y., Y.S., Y.M.); and Yokohama College of Pharmacy, Tozuka-ku, Yokohama, Japan (Y.O.)
Received for publication
April 22, 2008
Accepted
June 5, 2008.
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Abstract |
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). Increasing evidence indicates that the production and accumulation of Aβ cleaved from amyloid precursor protein (APP) is central to the pathogenesis of AD (Hardy and Selkoe, 2002). APP transgenic mice expressing various mutations identified from patients with familial AD have proven highly valuable in aiding our understanding of the cause and progression of AD (Ashe, 2001). For example, in Tg2576 mice overexpressing the Swedish mutation of the human APP (APP695 Swe), cognitive impairments are detectable at the age of 4 months with fear conditioning (Jacobsen et al., 2006), although amyloid plaques do not develop until the age of 9 months (Hsiao et al., 1996).
We have recently produced a new APP transgenic mouse line, APP-SL 7-5, that overexpresses human APP695 harboring the double Swedish and London mutations (Shin et al., 2007). APP-SL 7-5 Tg mice displayed spatial memory deficits as revealed by the Morris Water Maze test performed at ages ranging from 3 to 12 months. The AD model mice exhibit a small number of Aβ plaques in the hippocampus and entorhinal cortex at the age of 9 months and display considerable numbers of Aβ plaques at the age of 12 months and over (Shin et al., 2007). In the present study, we employed the aged APP-SL 7-5 Tg mice as a useful model to evaluate the beneficial effects of a natural compound on AD pathology as described below.
Large numbers of compounds from natural resources have provided novel leading compounds for drug development (Liu, 1993) as well as useful pharmacological tools (Ohizumi, 1997; Obara et al., 2002). In the course of our survey of materials having anti-AD drug activity from natural resources, we successfully found nobiletin, a polymethoxylated flavone from peels of Citrus depressa (Fig. 1), as a natural compound enhancing PKA/ERK/CREB signaling in cell culture systems, including cultured rat hippocampal neurons (Nagase et al., 2005a,b). Shortly thereafter, we have reported the capability of the natural compound to induce long-term potentiation via activating PKA-dependent phosphorylation of the 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit, GluR1, in the hippocampus in slices (Matsuzaki et al., 2008). It has been also demonstrated by us that nobiletin rescues Aβ-induced memory deterioration in AD model rats and exerts the preventive action on the Aβ-induced inhibition of phosphorylation of PKA and CREB in hippocampal neurons in culture (Matsuzaki et al., 2006). Furthermore, this natural compound improves impaired memory in olfactory-bulbectomized mice, accompanied by restoration of the olfactory-bulbectomized-induced cholinergic neurodegeneration (Nakajima et al., 2007a). In addition, nobiletin reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of ERK signaling in the hippocampus of mice (Nakajima et al., 2007b). These findings from our previous studies raise the possibility that the natural compound may have the ability to improve and/or prevent Aβ-induced memory impairment in a transgenic mouse model of AD overexpressing mutant human APP.
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; Rezai-Zadeh et al., 2005). However, it is unclear whether these natural compounds ameliorate the memory impairment in a transgenic mouse model of AD. Here we describe the first evidence that nobiletin not only prevents Aβ pathology but also improves the cognitive deficit in a transgenic mouse model of AD, APP-SL 7-5. |
Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). Tg mice expressing a double Swedish/London mutation (BE-APP695Sw/Lo) were generated on a C57/BL6 background. Line 7-5 for BE-APP695Sw/Lo (APP-SL 7-5) (n = 20) and age-matched wild-type C57/BL6 mice (n = 10) were used in this study. Animals were housed in cages with free access to food and water under the condition of constant temperature (23 ± 1°C) and humidity (55 ± 5%) and adapted to a standard 12-h light cycle/12-h dark cycle (light cycle: 9:00 AM to 9:00 PM). All experiments were performed according to the Guide for Care and Use of Experimental Animals (Tohoku University), in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institute of Health.
Drug Administration. Nobiletin was extracted and isolated as described previously (Nagase et al., 2005a). Nine-month-old APP-SL 7-5 Tg mice were separated randomly into two groups and administered nobiletin (10 mg/kg i.p.) or vehicle (0.5% Tween 80) daily for 4 months. The dose of nobiletin and the administration route were chosen on the basis of our previous study showing the memory improving effects of nobiletin (Nagase et al., 2005a; Matsuzaki et al., 2006; Nakajima et al., 2007a,b). Our quantitative analysis using high-performance liquid chromatography has shown that nobiletin crosses the blood-brain barrier (unpublished observation). During the course of the treatment for 4 months, one or two mice in vehicle- or nobiletin-treated APP-SL 7-5 Tg group died, respectively.
Open-Field Test. Mice were placed into the corner of a wooden box (50 x 50 x 40 cm) and allowed to freely explore for 10 min. The floor of the field was divided into 25 identical squares so that the ambulation of animals could be measured. The ambulation of the mice was measured by counting the number of times that the animals crossed from one square to another. The number of rearing and grooming events was also recorded. The scorer of the behavioral experiments was blind to treatment group.
Contextual Fear Conditioning. In the training session, mice were placed into a chamber with metal grids floor. Mice were allowed to freely explore for 2 min and were given an electric shock (2 s, 0.7 mA) from a metal grid floor at the end of the 2 min. The 2-min/2-s shock paradigm was repeated for a total of two shocks. After the last shock, animals were allowed to explore the context for an additional 1 min before removal from the training chamber. Freezing behavior, defined as cessation of all but respiratory movement, was measured by observing the animals every 5 s. Baseline freezing was established for the first 2 min of the training session. Freezing behavior was also recorded during the last 3 min of the training session (training). In the test session performed 24 h after training, mice were placed into the conditioned chamber for 5 min, and freezing behavior was measured manually (test).
Immunohistochemistry. After completion of the behavioral tests, all mice were deeply anesthetized with sodium pentobarbital and perfused transcardially with cold saline. The brains were rapidly removed and bisected through the midsagittal plane into each hemisphere. The lateral hemispheres were immersed in 10% buffered formalin for 2 to 3 days and embedded in paraffin for immunohistochemical analysis. The other hemispheres were frozen for subsequent use for sandwich enzyme-linked immunosorbent assays (ELISA) and Western blot analysis. Coronal sections were cut at 5 µm thickness from mouse brains. A series of adjacent sections were immunostained as described previously (Murayama et al., 1999) using antibodies to Aβ, including rabbit polyclonal antibody pAb4702 (Shin et al., 2007) and mouse mAb4G8 (Senetek, Maryland Heights, MO). Image analysis was conducted with AxioVision software (Carl Zeiss GmbH, Jena, Germany). For plaque quantification, two nonoverlapping and comparable coronal sections per animal were selected from vehicle- and nobiletin-treated APP-SL 7-5 Tg mice. An aggregation over 5 µm in diameter was recognized as an Aβ plaque. The percentage of the area of the hippocampus covered with plaques was calculated as plaque burden.
ELISA. The frozen mouse brain hemisphere was homogenized in lysis buffer (0.1 M Tris, pH 7.4, 0.1 M NaCl, 0.1 M phenylmethylsulfonyl fluoride, 1 µg/ml antipain, 1 µg/ml chymostatin, and 0.1 µg/ml leupeptin) and centrifuged at 350,000g for 20 min at 4°C. The pellet was sonicated in 6 M guanidine and centrifuged at 200,000g for 20 min at 4°C. Aβ1–40 and Aβ1–42 levels in the supernatant were measured by using a sensitive sandwich ELISA kit (Immuno-Biological Laboratories, Gunma, Japan).
Western Blot Analysis. The mouse brain homogenate was prepared as described above. SDS, NaF, and sodium orthovanadate (final concentration of 2%, 1 mM, and 1 mM, respectively) were added to the homogenate. The homogenate was then subjected to sonication and incubated on ice for 15 min. The mixture was centrifuged at 12,000g for 10 min, and the supernatant was collected. Equal amounts of protein (30 µg) were subjected to SDS-polyacrylamide gel electrophoresis (12.5% gels), and the blotted membrane was blocked in Tris-buffered saline with Tween 20 containing 5% skim milk for 1 h at room temperature as described previously (Nakajima et al., 2007b). The membrane was then incubated with anti-phospho-ERK (Thr202/Tyr204) antibody (Cell Signaling Technology, Beverly, MA) in 5% skim milk/Tris-buffered saline with Tween 20 overnight at 4°C and horseradish peroxidase-conjugated anti-rabbit IgG (Cell Signaling Technology) for 2 h at room temperature. After stripping of the antibody, the membrane was reprobed with anti-ERK antibody (Promega, Madison, WI). Immunoreactivities were visualized with SuperSignal West Pico Chemiluminescent Substrate (Pierce Chemical, Rockford, IL).
Statistical Analysis. The results are expressed as means ± S.E.M. Pairs of means were compared by unpaired two-tailed t test. Multiple means were analyzed by one-way ANOVA followed by the Tukey's post hoc test. A level of p < 0.05 was considered statistically significant.
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Results |
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), 9-month-old APP-SL 7-5 Tg mice were administered nobiletin daily for 4 months. We carefully monitored the general health of the mice throughout the course of the treatment with nobiletin and did not observe any adverse changes, nor did we observe significant weight changes. After 4 months of the daily administration of nobiletin, we first examined the effects of nobiletin on general behaviors in the open-field test. We evaluated the number of passed squares and rearings as horizontal and vertical movement activities. The number of crossed squares was decreased in vehicle-treated APP-SL 7-5 Tg mice compared with wild-type mice [F(2,24) = 10.958, p = 0.0004 by one-way ANOVA] (Fig. 2A). In addition, vehicle- and nobiletin-treated APP-SL 7-5 Tg mice showed a marked decrease in the number of rearings [F(2,24) = 13.279, p = 0.0001 by one-way ANOVA; p < 0.01, p < 0.001 versus wild-type mice by post hoc, respectively] (Fig. 2B). There were no significant differences in the number of grooming behaviors between groups [F(2,24) = 0.3434, p = 0.7128] (Fig. 2C). In addition, there were no significant differences in vertical and horizontal activities between vehicle- and nobiletin-treated APP-SL 7-5 Tg mice, suggesting that treatment with nobiletin did not affect general behaviors in APP-SL 7-5 Tg mice.
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; Atkins et al., 1998). In the training session, there were no significant differences in freezing responses between groups [basal: F(2,23) = 2.2376, p = 0.1294; training: F(2,23) = 2.9934, p = 0.0699] (Fig. 3). In the test session performed 24 h after training, APP-SL 7-5 Tg mice showed less freezing behavior than wild-type mice [F(2,23) = 14.428, p < 0.0001 by one-way ANOVA, p < 0.001 by post hoc] (Fig. 3). Treatment with nobiletin significantly reversed the memory impairments in APP-SL 7-5 Tg mice (p < 0.05 by post hoc).
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Nobiletin Improves Aβ Pathology in APP-SL 7-5 Tg Mice. All mice were sacrificed after completion of the behavioral tests, and their brains were isolated and processed for neuropathological or biochemical evaluations. To determine the effects of the long-term administration of nobiletin on Aβ deposition, we immunostained the brain sections from vehicle- and nobiletin-treated APP-SL 7-5 Tg mice with anti-Aβ antibody. At the age of 13 months, APP-SL 7-5 Tg mice expressed a considerable number of Aβ deposits throughout the cortex and hippocampus. Since the contextual fear conditioning paradigm has been previously shown to be hippocampal-dependent (Logue et al., 1997), we quantitatively analyzed the Aβ deposition in the hippocampus. It is noteworthy that daily treatment with nobiletin for 4 months reduced Aβ deposition in the hippocampus of APP-SL 7-5 Tg mice (Fig. 4A). Our quantitative analysis of Aβ deposition demonstrated that the treatment with nobiletin resulted in 
60% decrease in the area occupied by plaques compared with vehicle-treated APP-SL 7-5 Tg mice (p = 0.024) (Fig. 4B).
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Increasing Effects of Nobiletin Treatment on Phosphorylation of ERK in the Brains of APP-SL 7-5 Tg Mice. The ERK signaling is known to play a critical role in synaptic plasticity, learning, and memory (English and Sweatt, 1997; Atkins et al., 1998). It has been suggested that ERK signaling is dysregulated in the brains of AD patients as well as the brains of APP Tg mice (Dineley et al., 2001; Webster et al., 2006; Ma et al., 2007). Therefore, we next examined the effects of nobiletin on the phosphorylation of ERK, required for the activation of ERK signaling, in the brains of APP-SL 7-5 Tg mice. There were no significant differences in the levels of phospho-ERK between wild-type mice and vehicle-treated APP-SL 7-5 Tg mice (Fig. 5, A and B). In contrast, we found a marked and significant increase in the levels of phosphorylated ERK in nobiletin-treated APP-SL 7-5 Tg mice compared with vehicle-treated ones [F(2,17) = 4.0194, p = 0.0372 by one-way ANOVA, p < 0.05 by post hoc] (Fig. 5, A and B).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Plaque formation, the various Aβ species, and their correlation with cognitive decline in AD are still a matter of considerable debate in AD research. Some authors suggest that the accumulation and deposition of Aβ peptides and the subsequent formation of senile plaques are the primary cause of neurodegeneration and behavioral changes in AD patients (Kisilevsky and Fraser, 1997; Selkoe, 2001; Hardy and Selkoe, 2002). Several studies, however, have indicated that Aβ plaque burden does not correlate with dementia in patients (Arriagada et al., 1992; Samuel et al., 1994; McLean et al., 1999), and investigations using murine AD models have so far been unable to provide a clear answer to this question. Therefore, although nobiletin reduces Aβ plaque pathology and improves cognitive deficits in a transgenic mouse model of AD, it is not determined whether a reduction in Aβ production or deposition is responsible for the improvement of cognitive deficits by nobiletin. Recently, it has been demonstrated that soluble amyloid products, notably oligomeric Aβ, induce memory impairment in Tg2576 AD model mice (Lesné et al., 2006). Our preliminary results showed that treatment with nobiletin reduced the SDS-soluble Aβ levels in the brains of Tg2576 mice (unpublished observation). In addition, plasma Aβ levels were also reduced by nobiletin in this AD model mice (unpublished observation). Taken together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits and Aβ pathology in AD.
Activated ERK performs several functions relevant for establishing short- and long-term memory (Sweatt, 2004). In particular, ERK activation leads to a number of cellular changes associated with the development of long-term memory, such as alterations in gene expression and protein synthesis, dendritic spine stabilization, the modulation of ion channels, and changes in receptor trafficking. However, aberrant overexpression of ERK can lead to cell death (Zhuang and Schnellmann, 2006). Studies in AD brain suggest stage-dependent ERK activation followed by loss of active ERK (Webster et al., 2006). Similar to AD patients, Tg2576 AD model mice show activation of ERK at an early stage, whereas at the later stage, activated ERK is reduced by 20 months of age (Dineley et al., 2001). In this study, phospho-ERK levels in vehicle-treated APP-SL 7-5 Tg mice were comparable to those in wild-type mice at 13 months of age.
We have recently reported that nobiletin induces a sustained increase in phosphorylation of MEK and ERK in cultured hippocampal neurons as well as in PC12D cells (Nagase et al., 2005b). Nobiletin also inhibits the phosphodiesterase activity catalyzing the hydrolysis of cAMP, thereby increasing intracellular cAMP concentration to activate PKA in PC12D cells (Nagase et al., 2005b). It is well known that cAMP activates Rap1, a small GTP-binding protein in the Ras family that serves as a selective activator of B-Raf, in a PKA-dependent manner to stimulate B-Raf activity leading to activation of ERK (Vossler et al., 1997; Yao et al., 1998; York et al., 1998). Furthermore, this compound stimulates CREB phosphorylation and CRE-mediated transcription in a MEK/ERK-dependent signaling cascade (Nagase et al., 2005a,b). In the present study, we have shown that ERK phosphorylation is increased in nobiletin-treated APP-SL 7-5 Tg mice compared with vehicle-treated ones (Fig. 5). Given the important role of ERK activation in contextual fear conditioning (Atkins et al., 1998), it is plausible that the mechanism by which nobiletin improves memory impairment in APP-SL 7-5 Tg mice is, at least in part, mediated by ERK.
To elucidate the mechanism responsible for the reduction in Aβ following nobiletin administration, we analyzed APP processing by Western blot analysis using CT20, a C-terminal-specific APP antibody. Our preliminary results showed that nobiletin neither affected full-length APP levels nor the steady-state levels of APP C-terminal fragments C99 and C83 in the brains of APP-SL 7-5 Tg mice (unpublished observation). On the other hand, in our in vitro experiments, nobiletin significantly increased the activity of neprilysin (NEP), the dominant Aβ peptide-degrading enzyme in the brain (unpublished observation). It has been reported that NEP expression is enhanced during phorbol ester-induced differentiation of BeWo choriocarcinoma cells through a MEK/ERK-dependent signaling pathway (Suzuki et al., 2002). Another study, however, has shown that PKC activation, accompanied by activation of ERK, has no significant effects on NEP expression in SH-SY5Y cells (Yang et al., 2007). Further analysis of the effects of nobiletin on metabolism of Aβ peptide as well as APP processing is necessary to clarify the mechanism by which nobiletin reduces the Aβ pathology in the brains of APP-SL 7-5 Tg mice.
The focal deposits of Aβ elicit a significant microglial-mediated inflammatory response in the brain. It has been reported that nobiletin has inhibitory effects on phorbol ester-induced skin inflammation (Murakami et al., 2000). Our preliminary results also showed that nobiletin suppressed lipopolysaccharide-induced cyclooxygenase-2 expression in C6 rat glioma cells (unpublished observation). Therefore, it is possible that nobiletin may inhibit an inflammatory response elicited by extensive amyloid deposition in the brains of APP-SL 7-5 Tg mice.
Both abnormal horizontal and vertical activities have been observed in several lines of APP Tg mice expressing high levels of human Aβ. For example, Tg2576 mice, which overexpress the Swedish mutant form of human APP695, showed hyperactivity in the open-field test (Kobayashi and Chen, 2005). In contrast, APP23 mice overexpressing human APP751 with the Swedish mutation showed decreased ambulatory activity (Van Dam et al., 2003). In this study, we have consistently observed decreased horizontal and vertical activity in the APP-SL 7-5 Tg mice and found a trend toward normal horizontal activity in the nobiletin-treated group.
In summary, the present study has demonstrated that chronic treatment with nobiletin, a natural compound derived from citrus peels, improves the memory impairment and reduces the Aβ levels and plaques characterizing neuropathologically AD, suggesting that this natural compound has potential to become a novel drug for the treatment and prevention of AD. Further works, including clinical trials in AD patients, will be necessary to determine whether nobiletin will produce a similar therapeutic efficacy as was observed in a transgenic AD model mouse in the present study.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: AD, Alzheimer's Disease; Aβ, β-amyloid; APP, amyloid precursor protein; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated kinase; NEP, neprilysin; Tg, transgenic; PKA, protein kinase A; ELISA, enzyme-linked immunosorbent assay; ANOVA, analysis of variance; MEK, mitogen-activated protein kinase kinase.
Address correspondence to: Dr. Tohru Yamakuni, Division of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: yamakuni{at}mail.pharm.tohoku.ac.jp
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