Article pubs.acs.org/JAFC
Oral Administration of Soy Peptides Suppresses Cognitive Decline by Induction of Neurotrophic Factors in SAMP8 Mice Shigeru Katayama, Rie Imai, Haruka Sugiyama, and Soichiro Nakamura* Department of Bioscience and Biotechnology, Shinshu University, 8304 Minamiminowa, Ina, Nagano 399-4598, Japan ABSTRACT: SAMP8 mice have a shorter lifespan and show the dysfunction of the central nervous system. We here investigated whether soy peptides (SP) composed mainly of di- and tripeptides has the potential to prevent age-dependent cognitive impairment. SAMP8 and normal aging mice, SAMR1, were fed a diet supplemented with SP or a control diet for 26 weeks to investigate the preventive effects on the progression of cognitive decline using the Morris water maze. The SP-fed groups in SAMP8 and SAMR1 prevented the decline of cognitive ability compared to their controls. Increased expression of neurotrophic factors such as BDNF and NT-3 at mRNA and protein levels were observed in the brain of SP-fed mice, especially SAMP8. Further, the phosphorylated CREB protein level of SAMP8 was markedly up-regulated by SP feeding. These suggest that SPs have the potential for prevention of cognitive impairment via neurotrophic effects. KEYWORDS: soy peptides, SAMP8, cognitive impairment, neurotrophins, CREB
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INTRODUCTION Aging is an inevitable part of life for humans and is associated with declining physical and functional capacity of tissues and organs. Particularly, mild cognitive impairment and dementia has emerged as a major problem of disability in old age. The dietary intake of vegetables and fruit containing various phytochemicals contributes to maintaining good health and quality of life during the aging process.1,2 In recent years, there has been increasing interest in screening potent agents for the prevention and treatment of mild cognitive impairment and dementia from naturally occurring compounds. Senescence-accelerated mouse (SAM) was established as a model of accelerated aging by Takeda et al.3 and SAM prone 8 (SAMP8) spontaneously shows age-related behavioral disorders, including shortened life span, cognition impairment, and loss of hair. Particularly, SAMP8 has been recognized as a suitable animal model of age-related deficits in learning and memory at old age.4 To date, SAMP8 has been widely used in gerontological research. Several studies have suggested that phytochemicals such as docosahexaenoic acid,5 ginsenoside,6 and catechin7 attenuate memory impairment with aging. It has been demonstrated that these phytochemicals affect the upregulation of synaptic plasticity-related proteins, including brain-derived neurotrophic factor (BDNF) and cyclic AMP response element binding protein (CREB) that are critical for learning and memory formation.8 Cognition decline is believed to deteriorate initially because of dysfunctions of synaptic plasticity. Therefore, the induction of neurotrophic factors seems to contribute to the prevention of the age-related cognition decline. On the other hand, several agents such as resveratrol9 and proanthocyanidins10 have been shown to not only improve cognitive deficits but also increase lifespan in SAMP8 by Sirtuin 1 (SIRT1) activation. The induction of prosurvival factors such as SIRT1 also would be a potential strategy for the prevention of aging and age-related disorders. Soybean protein has been used as a source of nutrients in Asian countries for many decades. Soybean protein is well-known © 2014 American Chemical Society
for different functional properties and is widely recognized as a potential source of bioactive peptides. Soy peptides (SP) have been shown to exhibit a number of functional properties, including hypocholesterolemic,11 antihypertensive,12 antiviral,13 and anti-inflammatory14 effects. Recent studies have demonstrated the positive effects of SP on brain function. The intake of SP is reported to improve cognitive dysfunction in subjects with mild cognitive impairment as well as alleviate central fatigue, promote relaxation, and modulate the electroencephalogram.15 Furthermore, it has been shown that the ingestion of SP modulates cellular immune systems, regulate neurotransmitters, and boost brain function in healthy volunteers.16 However, it remains unknown whether SPs have beneficial effects on cognition in age-related cognitive decline. The purpose of the present study is to investigate the effects of SP oral administration on brain function of SAMP8 and normal aging control SAM resistant 1 (SAMR1) mice.
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MATERIALS AND METHODS
Materials. SP used in this study was a peptide mixture, which was composed primarily of di- and tripeptides (64.1%) and was kindly supplied by Fuji Oil Co. Ltd. (Osaka, Japan). The composition of the SP powder was as follows: 4.4% moisture, 86.7% protein, and 5.5% ash. All other chemicals were of analytical reagent grade. Animals. Male SAMP8 and SAMR1 mice were purchased from Japan SLC, Inc. (Shizuoka, Japan). All mice were individually housed and kept under conditions of controlled temperature (20−23 °C), humidity (40−70%), and a light/darkness cycle of 12 h/12 h (light on at 8:00 a.m.). All experiments were conducted in accordance with the institutional guidelines established by Shinshu University for the care and use of laboratory animals. Animal Protocol. Sixteen-week-old male SAMP8 and SAMR1 were used in this study. Animal were divided into four groups: (1) SAMP8 control (n = 12), (2) SAMP8 SP (n = 12), (3) SAMR1 Received: Revised: Accepted: Published: 3563
December March 27, March 30, March 31,
1, 2013 2014 2014 2014
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Table 1. Composition of the Experimental Diets (g/kg)
a b
ingredient
control diet
soy peptides (SP) diet
casein SP L-cystein constarch α-constarch sucrose soybean oil cellulose mineral mixturea vitamin mixtureb choline bitartrate tert-butylhydroquinone
140.0 − 1.8 465.7 155.0 100.0 40.0 50.0 35.0 10.0 2.5 0.008
70.0 70.0 1.8 465.7 155.0 100.0 40.0 50.0 35.0 10.0 2.5 0.008
Figure 1. Effect of soy peptides (SP) oral administration for 26 weeks on spatial learning and memory ability during the training trial sessions of the Morris water maze performance in SAMP8 and SAMR1 mice. Escape latency was used as a measure of spatial leaning in the platform task. Data are expressed as means ± SEM.
Mineral mixture, AIN-93 M (Oriental Yeast Corp., Tokyo, Japan). Vitamin mixture, AIN-93 (Oriental Yeast Corp., Tokyo, Japan).
control (n = 8) and (4) SAMR1 SP (n = 8). The control group was fed a normal AIN-93 M diet (Oriental Yeast, Tokyo, Japan) and the SP group was fed a SP diet containing 7% (w/w) SP (Table 1). The mice were allowed free access to the diet and tap water. Food intake and body weight were measured once a week. After 26 weeks, all mice were tested in the Morris water maze and then sacrificed. The brain was rapidly excised and quickly put on ice. These tissues were soaked in RNA later (Sigma-Aldrich, St. Louis, MO) and RIPA lysis buffer (Santa Cruz Biotechnology, Santa Cruz, CA) for RNA isolation and Western blot, respectively, and then stored at −80 °C until use. Morris Water Maze for Cognitive Testing. Spatial learning and memory of animals were tested in a Morris water maze.17 A circular plastic pool (diameter, 120 cm; height, 50 cm) was filled with water kept at 25 ± 1 °C. An escape platform (diameter, 11 cm) was hidden 1 cm below the surface of water on a fixed location in the pool. On training trials, the mice were given four trials per session for 7 subsequent days in the presence of the platform, each trial having a ceiling time of 60 s and a trial interval of approximately 20 s. When mice found the platform, they were allowed to stay on it for 20 s. The mice that did not find the platform within 60 s were placed on the platform for 20 s at the end of trial. One day after the last training trial sessions, mice were subjected to a probe trial session in which the platform was removed from the pool. The mice were allowed to swim for 120 s to search for it. Escape latency time (the first time that the mice crossed the former platform) and time in target quadrant (time searching the pool quadrant where the platform had been) were recorded and analyzed by an overhead camera and ANY-maze video tracking system software (Stoelting Co., Wood Dale, IL). RNA Isolation. Total RNA was isolated from the tissues of each mouse using RNAiso Plus (TaKaRa Bio, Shiga, Japan) according to the manufacturer’s instructions. Briefly, brain tissues were homogenized in RNAiso Plus. Total RNA was extracted with the phenolchloroform method, followed by isopropyl alcohol precipitation and ethanol washing. cDNA was synthesized using a Rever Tra Ace qPCR RT kit (Toyobo, Osaka, Japan) according to the manufacturer’s instructions. Real-Time PCR Quantification. Quantification of relative gene expression was performed by real-time quantitative PCR, using a StepOne Real-time PCR System (Applied BioSystems, Foster City, CA). Real-time PCR was carried out using the Kapa SYBR Fast qPCR kit (Kapa Biosystems, Woburn, MA). Quantitative PCR was carried out using the thermal cycling program, which consisted of one cycle at 95 °C for 3 min, 40 three-segment cycles (95 °C for 3 s and 60 °C for 20 s), and a final dissociation cycle (95 °C for 15 s and stepwise increase from 60 to 95 °C). To normalize the amount of total RNA present in each reaction, β-actin was used as an internal standard, and the expression in the experimental group was expressed as folds of SAMP8 controls using the comparative Ct method. The primer sequences were as follows: NGF: 5′-CAAGCGTTGACAACAGATGA-3′ (forward) and 5′-CAGCCTCTTCTTGTAGCCTTCC-3′
Figure 2. Effect of SP oral administration for 26 weeks on spatial learning and memory ability during the probe trial session of the Morris water maze performance in SAMP8 and SAMR1 mice. (A) Escape latency and (B) time in target quadrant were used as a measure of spatial leaning in the hidden platform task. Data are expressed as means ± SEM *p < 0.05: significantly different from control. (reverse), BDNF: 5′-GCGGCAGATAAAAAGACTGC-3′ (forward) and 5′-CTTATGAATCGCCAGCCAAT-3′ (reverse), NT-3: 5′-TTTCTCGCTTATCTCCGTGGCATCC-3′ (forward) and 5′-GGCAGGGTGCTCTGGTAATTTTCCT-3′ (reverse), SIRT1: 5′-TGACCGATGGACTCCTCACT-3′ (forward) and 5′-ACAATCTGCCACAGCGTCAT-3′ (reverse), and β-actin: 5′-GCGGCAAAGACAAGAAAAAG-3′ (forward) and 5′-GAAGTGGTCCTCCCAGTCAT-3′ (reverse). Western Blotting Analysis. The brain tissues were homogenized in RIPA lysis buffer according to standard procedures and centrifuged 3564
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Figure 3. Effect of SP oral administration on mRNA expressions of (A) NGF, (B) BDNF, (C) NT-3, and (D) SIRT1 in the brain from SAMP8 and SAMR1 mice. Data are expressed as means ± SEM *p < 0.05: significantly different from control.
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at 12 000 rpm for 10 min at 4 °C. The supernatants were collected and protein concentration was determined using the BCA protein assay with bovine serum albumin as standard. Levels of NGF, BDNF, NT-3, CREB, and Ser-133 phosphorylated CREB, extracellular-regulated kinase1/2 (ERK1/2), and Thr-185/Tyr-187 phosphorylated ERK1/2 were analyzed by Western Blot. Briefly, protein samples (12.5 μg) were electrophoresed on 15% polyacrylamide gels and blotted onto polyvinylidene fluoride membranes (Clear Blot Membrane-P; ATTO, Tokyo, Japan). Blots were incubated with antibodies against NGF (1:500, Abcam, Cambridge, MA), BDNF (1:1000, Sigma-Aldrich), NT-3 (1:250, Abcam), CREB (1:750, Abcam), Ser-133 phosphorylated CREB (1:500, Abcam), ERK1/2 (1:500, Enzo Life Sciences, Farmingdale, NY), phosphorylated ERK1/2 (1:1000, Enzo), and βactin (1:5000, Sigma-Aldrich), followed by antirabbit IgG horseradish peroxidase-conjugate (1:5000, Anaspec, San Jose, CA). Chemiluminescence detection was performed using Pierce Western blotting substrate (Thermo Scientific, Rockford, IL) and AE-9300 Ez-Capture (ATTO). β-Actin was used as an internal control for Western Blot. Immunostaining. The harvested brains were washed once in cold PBS to remove blood and fixed with 30% paraformaldehyde. The tissues were embedded in paraffin and sectioned at a thickness of 6 μm. Following blocking with 10% goat serum in PBS containing 0.1% Tween 20, the sections were incubated with antibody against NT-3 (1:750, Abcam, Cambridge, MA). After rinsing six times with 0.1% BSA in PBS, samples were further incubated the secondary antibody, Alexa Fluor 488 goat antirabbit IgG (H&L) (1:1000, Abcam). After rinsing six times with 0.1% BSA in PBS, the sections were mounted with immunoselect antifading mounting medium DAPI (Dianova, Hamburg, Germany). We acquired images with an EVOS fluorescence microscope (EVOS fl; Advanced Microscopy Group, Bothell, WA). Statistical Analysis. Data are presented as mean ± SEM the training session data in Morris water maze were analyzed by two-way ANOVA and the other data were analyzed with Student t test. A level of p < 0.05 was considered significant.
RESULTS SAMP8 and SAMR1 were fed control or SP for 26 weeks from 16 weeks of age. Dietary food intake and weight gain did not differ among groups throughout the experiments (data not shown). The Morris water maze test was performed to investigate the effects of a prolonged consumption of SP on the decline in spatial memory and learning abilities of SAMP8 and SAMR1. The probe trial was performed the day after completing the 7-day training trial. In the Morris water-maze training session, SAMR1 rapidly learned the location of the platform, whereas SAMP8 had longer escape latency on every test days compared to SAMR1 (Figure 1). No significant decrease in escape latency was observed between control and SP-fed groups of SAMP8. In contrast, the escape latency of SP-fed SAMR1 mice was shortened compared to that of control mice; however, there was no statistical difference. In the probe trial, the escape latency of SP-fed SAMP8 and SAMR1 mice was faster than that of their controls (Figure 2A). Statistically significant decrease in escape latency was observed in the SP-fed SAMR1 groups. On the other hand, SP-fed SAMP8 mice spent significantly more time in the target quadrant as compared to control mice (Figure 2B). We next examined whether SP feeding can modulate the expression of neurotrophic and longevity factors in the brain (Figure 3). The mRNA expression of NGF, BDNF, and NT-3 in SAMP8 and SAMR1 mice was up-regulated by SP feeding. Among them, a statistical significant increase of NT-3 expression was found in both SP-fed groups of SAMP8 and SAMR1. On the other hand, an increase in the mRNA expression of SIRT1 was observed in the SP-fed SAMR1, but not SP-fed SAMP8. 3565
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Figure 5. Localization of NT-3 in the hippocampus containing the CA1 layer was examined using immunostaining. Scale bar: 100 μm.
CREB activation occurs (Figure 6). A significant increase in the phosphorylated CREB was observed in the brain of SP-fed SAMP8 group compared with the control group. The phosphorylated ERK1/2 of SP-fed SAMP8 group was increased compared with that of the control group, although this was not statistically significant.
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DISCUSSION Recently, much attention has been focused on a potential neuromodulatory functions and brain protective properties of naturally occurring compounds. Our study demonstrated that the SP-fed mice improved spatial learning and memory when compared with the control mice. The interesting finding of the present study is the significant up-regulation of neurotrophic factors such as NGF, BDNF, and NT-3, which promote neurogenesis, neurodifferentiation, neuroprotection, and neuroplasticity.18 NT-3 is widely distributed throughout both the peripheral and central nervous system19 and plays a crucial role in the promotion of neuronal survival and nerve fiber outgrowth and in the enhancement of regeneration of damaged nerve.20 Thus, the NT-3 enhancement in the brain is a potential therapeutic strategy for preventing age-related cognitive decline. Generally, BDNF exerts multiple cellular functions, including the protective effects on crucial neuronal circuitry involved in Alzheimer’s disease (AD).21 Previous studies have been demonstrated that Ginkgolide B inhibits Aβ (25−35)-induced apoptosis in hippoicampal neurons via up-regulation of BDNF expression.22 Further, resveratrol treatment enhanced the generation of newborn neurons in dentate gyrus and restored the decreased hippocampal BDNF level significantly in prenatally stressed rat brain.23 The present study suggests that it is possible to use SPs to prevent degenerative neurological disorders of aging because SPs have minor side effects. It is well-known that the dysregulation of adult neurogenesis progresses in AD patients and in various AD model mice.24,25 Thus, neurotrophic agents may have therapeutic potential for prevention and treatment of AD. This study showed that SP administration resulted in an increased SIRT1 expression level of SAMR1 mice. Sirtuin activity has been shown to play a significant role in promoting longevity, preventing disease and increasing cell survival.26 Thus, the up-regulation of SIRT1 might contribute to the protective effect on cognitive decline in SP-fed SAMR1.
Figure 4. Effect of SP oral administration on protein level of NGF, BDNF, and NT-3 in the brain of SAMP8 and SAMR1 mice. (A) Representative images of Western blotting. (B) Densitometric quantification of band intensities. Data are expressed as means ± SEM *p < 0.05: significantly different from control.
The protein levels of NGF, BDNF, and NT-3 in the brain was analyzed using Western blotting (Figure 4). There was a significant increase in BDNF and NT-3 protein levels of SP-fed SAMP8 group compared to control group, whereas no increase was observed in SP-fed SAMR1 group. In contrast, a significant increase in the NGF protein level was observed in SP-fed SAMR1, but not SP-fed SAMP8. Since the hippocampus is important for many aspects of learning and memory, the localization of NT-3 in the hippocampus was examined using immunostaining followed by fluorescence microscopy (Figure 5). NT-3 protein expression was confirmed in the hippocampus of SAMP8 mice. Further, the phosphorylated level of transcription factor CREB in brain was examined to demonstrate whether 3566
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and memory formation.29,30 However, no significant increase in phosphorylated ERK protein levels was observed in this study. A number of kinases, including protein kinase A protein kinase C, and AKT, are also known to be phosphorylate and activate CREB.31 Therefore, it seems that another signaling pathway exists in the activation of CREB by SP feeding. Further investigation is needed to explore the signal transduction cascade to induce the neurotrophic factors in the SP-fed SAMP8 group. In the experiment of water maze task, no significant difference in escape latency was observed between control and SPfed groups in the training session in both SAMP8 and SAMR1. However, a significant difference was observed in the probe trials in escape latency of SAMR1 and in time in target quadrant of SAMP8. This discrepancy is caused by a difference of the time-limit between training session and probe trials, which were 60 and 120 s, respectively. In particular, since SAMP8 at 42 weeks were not quick in movement, they needed more time compared to SAMR1. Therefore, it is considered that the measurement of time in the target quadrant is suitable to evaluate the spatial learning and memory ability of SAMP8. Taking these results into consideration, our data support that the SP feeding could affect the memory function of both SAMP8 and SAMR1. In the present study, we used SAMP8 mice as a model of age-related cognition disorder and SAMR1 mice as normal aging control mice. Indeed, SAMP8 showed not only greater decline in performance in the Morris water maze but also decreased expression levels of neurotrophic factors. A significant increase of SIRT1 mRNA was found in only SPfed SAMR1, while a significant increase of pCREB was found in only SP-fed SAMP8. These results suggest that the working point of SP feeding in SAMP8 is different from that of SAMR1. It is reasonable to assume that this difference was caused by different gene expression profiles of receptors and coregulators. The SP used in this study was composed mainly di- and tripeptides, and this peptide mixture have been reported to increase the serum levels of amino acids more rapidly than the original soy proteins or an amino acid mixture of equivalent composition.32 It was also shown that short-term oral intake of SP increases neuroactive amino acids such as the neurotransmitter L-glutamate, its precursor L-glutamine, the neuromodulator D-asparatate, and branched-chain amino acids such as 33 L-valine, L-leucine, and L-isoleucine. Generally, dipeptides and tripeptides are absorbed by small intestinal cells in peptide form using the PepT1 peptide transporter and hydrolyzed by cellular enzymes and the resultant amino acids are transported across the serosal membrane. Taking these results into consideration, it appears possible that neuroactive amino acids produced from the SP exhibit an effective nutraceutical for promoting brain function. The mechanism for oligopeptide transport in the intestinal tract is not fully understood; however, Shimizu et al. demonstrated that antihypertensive tripeptide VPP transpiorted across human intestinal epithelial cells monolayers via the paracellular route, which is a nondegradation pathway.34 It is possible that the intact dipeptides directly contribute to the induction of neurotrophic factors. Further studies are needed to determine the mechanism of action and identify the active sequence of peptides. In conclusion, the present study has demonstrated that SPs have the potential for the prevention of cognitive impairment via the neurotrophic effects in SAMP8 mice. These results indicated that SP may play an important role for the prevention of age-related cognitive decline and neurodegenerative diseases such as AD.
Figure 6. Effect of SP oral administration on protein level of phosphorylated CREB and ERK1/2 in the brain from SAMP8 and SAMR1 mice. Data are expressed as means ± SEM *p < 0.05: significantly different from control.
Porquet et al.9 have demonstrated that SIRT1 activation by long-term dietary resveratrol not only reduces cognitive impairment but also increases mean life expectancy and maximal life span in SAMP8 and SAMR1. During our experiment, there were no deaths in SAMR1 mice; however, the upregulation of SIRT1 expression by dietary SP may affect the longevity of SAMR1 mice. Neurotrophic factors termed neurotrophins (NGF, BDNF, NT-3, and NT-4/5) play an important role in the growth and survival of neurons. CREB is a transcription factor implicated in the control of adaptive neuronal responses and the regulation of neurotrophic genes.27,28 This study suggests that increased gene expression of NGF, BDNF, and NT-3 observed in SP-fed SAMP8 group was accompanied by activation of CREBdependent pathways. The induction of neurotrophic factors by SP feeding could contribute to a protective effect on cognitive decline in SAMP8. Recent work suggests that the transactivation of CREB was mainly caused by the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK), which plays an important role in long-term synaptic plasticity 3567
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AUTHOR INFORMATION
Corresponding Author
*Tel & Fax: +81-265-77-1609. E-mail:
[email protected]. jp. Notes
The authors declare no competing financial interest.
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ABBREVIATIONS USED AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein; ERK, extracellular-regulated kinase; MAPK, mitogen-activated protein kinase; NGF, neuron growth factor; NT-3, neurotrophin-3; SAMP8, senescence-accelerated mice prone 8; SAMR1, senescence-accelerated resistant mouse 1; SIRT1, Sirtuin 1; SP, soy peptides
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Journal of Agricultural and Food Chemistry
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dx.doi.org/10.1021/jf405416s | J. Agric. Food Chem. 2014, 62, 3563−3569
