Fructooligosaccharides Ameliorating Cognitive Deficits and

Article Cite This: J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Fructooligosaccharides Ameliorating Cognitive Deficits and Neurodegeneration in APP/PS1 Transgenic Mice through Modulating Gut Microbiota Jing Sun,†,# Suzhi Liu,‡,# Zongxin Ling,§ Fangyan Wang,∥ Yi Ling,† Tianyu Gong,⊥ Na Fang,⊥ Shiqing Ye,⊥ Jue Si,⊥ and Jiaming Liu*,⊥,†

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†

Department of Neurology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China ‡ Department of Neurology, The Affiliated Taizhou Hospital, Wenzhou Medical University, 150# Ximen Road, Linhai District, Taizhou 317000, Zhejiang China § Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China ∥ Departments of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China ⊥ Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China S Supporting Information *

ABSTRACT: Alzheimer’s disease (AD) is closely related to gut microbial alteration. Prebiotic fructooligosaccharides (FOS) play major roles by regulating gut microbiota. The present study aimed to explore the effect and mechanism of FOS protection against AD via regulating gut microbiota. Male Apse/PSEN 1dE9 (APP/PS1) transgenic (Tg) mice were administrated with FOS for 6 weeks. Cognitive deficits and amyloid deposition were evaluated. The levels of synaptic plasticity markers including postsynaptic density protein 95 (PSD-95) and synapsin I, as well as phosphorylation of c-Jun N-terminal kinase (JNK), were determined. The intestinal microbial constituent was detected by 16S rRNA sequencing. Moreover, the levels of glucagon-like peptide-1 (GLP-1) in the gut and GLP-1 receptor (GLP-1R) in the brain were measured. The results indicated that FOS treatment ameliorated cognitive deficits and pathological changes in the Tg mice. FOS significantly upregulated the expression levels of synapsin I and PSD-95, as well as decreased phosphorylated level of JNK. The sequencing results showed that FOS reversed the altered microbial composition. Furthermore, FOS increased the level of GLP-1 and decreased the level of GLP-1R in the Tg mice. These findings indicated that FOS exerted beneficial effects against AD via regulating the gut microbiota-GLP1/GLP-1R pathway. KEYWORDS: Alzheimer’s disease, fructooligosaccharides, cognitive deficits, synaptic plasticity, gut microbiota

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INTRODUCTION Alzheimer’s disease (AD) is a progressive neurodegenerative condition with cognitive decline.1,2 A synaptic plasticity dysfunction, β-Amyloid (Aβ) accumulation, and abnormally phosphorylated tubulin-associated unit (Tau) protein are mainly the pathogenesis of AD.3,4 So far there are still no effective therapies available for AD. Altered gut microbiota increased the risk of AD5,6 and may boost the AD pathogenesis.7−9 The gut microbiota of AD patients were different from that of health control, which was characterized by abundant Bacteroides, Actinobacteria, and Selenomonadales.9 Moreover, the gut microbiota in APPswe/PS 1dE9 (APP/ PS1) transgenic (Tg) mice were disturbed7 and were characterized by increasing the family level of Helicobacteraceae and Desulfovibrionaceae and genus level of Odoribacter and Helicobacter.8 The germ-free (GF) mouse with colonization of gut microbiota from APP transgenic mice could contribute to cerebral Aβ pathology, while that with colonization of gut © XXXX American Chemical Society

microbiota from wild-type (WT) mouse could not result in Aβ accumulation.10 Recent studies have indicated that probiotics/ probiotic treatment improved cognitive impairment via gut microbiota−gut brain axis.6,7,9,11 Our previous studies demonstrated that probiotics Clostridium butyricum treatments were effective for depression,12 vascular dementia,13 diabetes complications,14 and traumatic brain injury in mice.15 Therefore, targeting modulation of gut microbiota may be feasible for AD. Prebiotics are dietary supplements that offer a health benefit involved with regulation of the gut microbiota.16 Prebiotic fructooligosaccharides (FOS) are found in natural fruits and vegetables such as wheat, apple, and onion, which can boost the Received: December 31, 2018 Revised: February 17, 2019 Accepted: February 20, 2019

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DOI: 10.1021/acs.jafc.8b07313 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Article

Journal of Agricultural and Food Chemistry

symmetrically placed in the center of the box on days 3−4. On the fifth day, mice were returned to the area with one familiar object (3 cm × 2 cm × 3 cm cuboid) and one novel object (2 cm × 3 cm cylinder). A mouse freely explored the objects for 5 min. The time spent on familiar objects (TF) and novel objects (TN) were recorded. Exploration was defined as sniffing (within 1 cm), pawing, or biting the object, but not leaning against or standing on the object. A discrimination index (DI) index was calculated as follows: DI = (TN − TF)/(TN + TF) × 100%. Western Blot Analysis. After behavioral assessments, mice were killed and the tissue samples of the brain were collected and were homogenized in buffer (RIPA, Beyotime Biotechnology, Shanghai, China). The homogenate was centrifuged at 12 000 × g, and the protein concentrations were determined according to our previous methods.14,15,34 The primary antibodies were PSD-95 (1:1000, Bioworld, Louis Park, MN, U.S.A.), synapsin I (1:1000, Bioworld, Louis Park, MN, U.S.A.), JNK (1:1000, Bioworld, Louis Park, MN, U.S.A.), JNK pThr183/pTyr185 (1:1000, Bioworld, Louis Park, MN, U.S.A.), and GLP-1R (1:1000, Bioworld, Louis Park, USA). The membrane was washed with Tris-buffered saline and incubated with secondary antibody at room temperature for 1 h. GAPDH was used as the loading control. Congo Red Staining and Immunohistochemistry. The brains were removed. The cortex was fixed, embedded, and then sectioned, according to our previous methods.12,14 The progress of Congo red staining was performed according to our previous study. For immunohistochemistry, the hippocampus and colon tissues of the mouse were removed. The tissues were fixed in formaldehyde, embedded into paraffin, and then sliced, according to our previous methods.12,15 The primary antibodies were GLP-1 primary antibody (1:250, Abcam, Cambridge, MA, U.S.A.), GLP-1R (1:200, Bioworld, Louis Park, MN, U.S.A.), PSD-95 (1:200, Bioworld, Louis Park, MN, U.S.A.) and synapsin I (1:200, Bioworld, Louis Park, MN, U.S.A.). Then the sections were incubated with secondary antibodies, visualized using diaminobenzidine (DAB) as the chromogen, and observed with a light microscope. The brown granules were defined as positive signals. Analysis of the Aβ42 Level in the Brain by ELISA. The brain was homogenized and used to measure the concentration of Aβ42 by using ELISA kits (Invitrogen Corporation, Camarillo, CA, U.S.A.) according to the instructions. The standard curve was established and then used to calculate the level of Aβ42 in the tissues. Values were expressed as ng/ mg. Fecal DNA Extraction and 16S rRNA Sequencing. The colonic contents (0.2−0.3 g per sample) were collected and stored at −80 °C for further detection. DNA extraction used Qiagen stool DNA extraction kit (QIAgen, Hilden, Germany). Illumina Miseq 2500 platform (Shanghai Majorbio Biopharm Technology Co., Ltd.) is used to amplify the V3−V4 region of the 16S rRNA gene. Principal component analysis (PCA), principal coordinate analysis (PCoA), heatmap of RDA-identified key Open-reference operational taxonomic unit (OTU), and arithmetic mean (UPGMA) were analyzed. Bioinformatic Analysis. The 16S rRNA sequencing data set generated by MiSeq operation is merged and decomposed into each sample using the QIIME version 1.9.0. OTU pick and then operated with USEARCH V7 referenced against the Greengenes database version 13.8, with a sequence similarity of 97%. OTUs with number less than 0.005% of the total sequence number were excluded. To discover biomarkers, linear discriminant analysis (LDA) effect size (LEfSe) was used to analyze the characteristics of gut microbiota. LEfSe detected the features with significant difference abundances between designated taxa with the methods of the Kruskal−Wallis rank sum test, and and LDA was performed to evaluate the effect on size of each characteristic. Statistical Analysis. The data were statistically analyzed by SPSS 18.0 (SPSS, Chicago, IL, U.S.A.). The escape latency data of the MWM were analyzed by ANOVA with repeated measures. Other data were analyzed by using one-way ANOVA followed by Tukey’s test. P < 0.05 was considered a statistical difference.

growth of beneficial gastrointestinal microbes such as Bif idobacterium and Lactobacillus.17,18 Prebiotics-induced promotion of these valuable agents was considered to have many beneficial effects on host health.19 In addition, Bif idobacterium and Lactobacillus have great effects on the gut−brain axis.20,21 The intake of Bimuno-galactooligosaccharides could reduce the waking-cortisol response, which is a biomarker of emotional disorders such as depression.22 Prebiotic oligosaccharides ameliorated cognitive impairment11 and modulated the intestinal microbial constituent and metabolism in the APP/ PS1 mice.23 Glucagon-like peptide-1 (GLP-1) secreted by Lcells in the gut is influenced by gut microbiota.24 L-cells are stimulated by direct contact with the gut microbiota. The change of the GLP-1 content was related to altered gut microbial.24 Prebiotics could also directly affect secretion of GLP-1.25,26 Recently our previous studies have shown that GLP1 could affect brain function via the gut−brain axis.12,15 GLP-1 could reduce the Aβ level in vitro.27−29 Furthermore, GLP-1 analogues, such as Exendin-4, could reduce the Aβ level and amyloid plaque deposition in AD model mouse.30 The aim of the present study was to determine whether FOS treatment could protect against the cognitive impairment, Aβ accumulation, synaptic plasticity dysfunction, and gut microbial alteration in AD model mice and to explore its mechanism via the prebiotic-gut microbiota-GLP-1 pathway.

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MATERIALS AND METHODS

Animals and FOS Treatment. Male APPswe/PS 1dE9 (APP/ PS1) transgenic (Tg) mice (6 months old) and matched wild type (WT) C57BL/6J mice were obtained from Nanjing Biomedical Research Institute of Nanjing University, Nanjing, China. The Tg mouse was used as the AD model animal, which expressed mutant APP and PS1. All animals were housed at 22 ± 2 °C of temperature and 55 ± 5% of humidity. All experiments procedures were approved by Animal Ethical Committee of Wenzhou Medical University. Tg mice were randomly divided into two groups (n = 8 per group): AD model group (Tg group) and FOS treatment group (Tg + FOS group). Tg + FOS group were treated with containing 2% (w/w) FOS (with a purity 95%−99%; Deang Biological Technology Ltd., Jiangmen, China) in the drinking water for 6 weeks, according to our preliminary experiments and related references.31,32 WT mice were also divided into two groups (n = 8 per group): WT control group (WT group) and FOS control group (WT + FOS group). Mice of Tg group and WT group received the same concentration vehicle (sodium carboxyl methyl cellulose, CMC-Na). All mice received normal food and were fed daily. Behavioral Evaluation. After drug treatment, the cognitive deficits were assessed with an open-field test (OFT),13 Morris water maze test (MWM),14 and object recognition test (ORT).33 Prior to all behavioral tests, all animals were kept in the experimental room for 1 h. The data were measured by independent observers. OFT. A mouse performed in an open arena (25 cm × 25 cm) with a floor divided into 16 equal squares, and the 4 squares in the middle were defined as the central zone. A mouse was in the center of the instrument and freely explored the arena for 5 min. The number and time of crossed squares were recorded. The device was cleaned with 70% alcohol and dried after each test to avoid the effect of odor on the next mouse. MWM. Morris water maze was composed of a cylindrical water tank (120 cm × 50 cm× 30 cm) filled with opaque water with a video capture system and data analysis system (DigBehv, Jiliang, China), which was divided into four imaginary quadrants. A platform (6 cm in diameter) was placed under water for 1 cm. In the first 5 days, a mouse was placed in the water and trained to seek the platform. The time spent was recorded as the escape latency. More than 60 s was recorded as 60 s. Then, the platform was removed from the water, and the mouse was recorded as the residence time in the quadrant of the former platform. ORT. A mouse was individually placed in a test box (25 cm × 25 cm × 35 cm) in the first 2 days. Two objects of the same material were B


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Figure 1. Effects of FOS on cognitive deficits in Tg mice. The peripheral active time (A), the peripheral travel distance (B), and active time in the open field test (C); escape latency (D) and the time spent in the target quadrant in the Morris water maze test (E); and recognition factor in the object recognition test (F). Error bars indicate the SEM; n = 6−8 for each group. *P < 0.05 vs WT group, **P < 0.01 vs WT group, #P < 0.05 vs Tg group, ##P < 0.01 vs Tg group.

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RESULTS FOS Treatment Alleviated Cognitive Deficits in the Tg Mice. In the OFT, the time and distance of peripheral activity and total activity time were recorded. The time and distance of peripheral activity in the Tg mice significantly decreased compared with that in WT mice (P < 0.01, Figure 1A,B). FOS significantly increased the time of peripheral activity in the Tg mice (P < 0.01, Figure 1A). Moreover, FOS treatment increased the distance of peripheral activity in Tg mice, while it had no significant difference (P > 0.05, Figure 1B). Compared with the WT mice, total activity times in Tg mice were significantly decreased (P < 0.01, Figure 1C), while FOS treatment reversed the effect (P < 0.05, Figure 1C). No statistical difference was observed between the WT group and the WT + FOS group (P > 0.05, Figure 1A,−C). During the test training, animals gradually learned to seek hidden platforms, and the escape latency was also gradually shortened in the MWM (Figure 1D). The escape latencies in the Tg mice were obviously longer than in the WT mice (P < 0.01, Figure 1D). The escape latencies of FOS-treated mice were significantly decreased, compared with the Tg mice (P < 0.01, Figure 1D). There was obvious reduction of the residence time in the quadrant in the Tg group compared to the WT group (P < 0.01, Figure 1E), while FOS treatment was much longer than that in the Tg group (P < 0.05, Figure 1E). In the ORT, the Tg mice failed to discriminate between the familiar and the novel objects, whereas the mice treated with FOS spent more time on the novel object than on the familiar object in the Tg mice. Compared with the WT mice, the discrimination index in the Tg mice was significantly decreased (P < 0.05, Figure 1F), while the FOS treatment significantly reversed this situation (P < 0.01, Figure 1F), indicating that FOS treatment improved cognitive impairment in the Tg mice. FOS Treatment Decreased Amyloid Deposition in the Tg Mice. Aβ deposition is one of the neurological hallmarks of AD. Congo red staining identifies amyloid deposition in the brain. As shown in Figure 2 A, the brick red patches indicated

amyloid deposition. The brick red patches had increased in the cortex of the Tg group. After FOS treatment, the brick red patches in Tg mice decreased, suggesting that FOS treatment could reduce amyloid deposition in the Tg mice. Aβ is the main component of amyloid plaques. The Aβ42 level in the Tg group was significantly higher compared with the WT group (P < 0.01, Supporting Information Figure 1), whereas the level of Aβ42 in FOS-treated mice was dramatically decreased compared with the Tg mice (P < 0.05, Supporting Information Figure 1). FOS Treatment Suppressed JNK Activation in the Tg Mice. JNK pathways played a pivotal role in neurodegenerations. Western blot analysis showed an increase of p-JNK level in the Tg mice compared with WT mice (Figure 2 B), while the level of p-JNK was down-regulated after treatment with FOS (Figure 2 B). Compared with the Tg mice, the ratio of p-JNK/ JNK in the FOS-treated mice was significantly decreased (P < 0.01, Figure 2 B and C), indicating that FOS could inhibit JNK activation in the Tg mice. FOS Treatment Increased Levels of Synaptic Plasticity Related Proteins in the Tg Mice. To evaluate the synaptic plasticity, we detected the levels of PSD-95 and synapsin I by Western blot and immunohistochemistry. In Western blot, the levels of PSD-95 and synapsin I in the Tg group were significantly increased (PSD-95: P < 0.01, synapsin I: P < 0.05; Figure 3A,B), whereas that of the FOS-treated mice was significantly increased levels of PSD-95 and synapsin I (PSD-95: P < 0.05, synapsin I: P < 0.05; Figure 3A,B) compared with the WT group. In Immunohistochemistry, the levels of PSD-95 and synapsin I in Tg mice were lower than that in the WT mice, while that in FOS-treated mice were higher than that in Tg mice (Figure 3C−E). FOS Treatment Reversed the Altered Intestinal Microbial Composition in the Tg Mice. The overall microbial compositions were examined at different taxonomic levels. Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia were the dominant bacteria (Figure 4A). Proteobacteria in Tg mice significantly increased compared with the WT group (p = C


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Figure 2. Effects of FOS on the amyloid deposition and JNK signaling activity in Tg mice. Representative photomicrographs of the pathologic changes of Congo red staining in the cortex (A). Magnification 200×. Scale bar = 100 μm. Western blot analysis of p-JNK and JNK expression (B); levels were normalized to levels of the internal control (GAPDH). Quantitative analysis ratio of p-JNK/JNK (C); the reference value of the p-JNK/JNK was the ratio of the WT group. Error bars indicate SEM; n = 4−6 for each group. *P < 0.05 vs WT group, ##P < 0.01 vs Tg group.

and 5D, p = 0.1563). Bacteroidales_S24−7_group, Lachnospiraceae, Ruminococcaceae, Prevotellaceae, and Helicobacteraceae at the family level were the dominant bacteria (Figure 4D). Compared with the WT group, Helicobacteraceae and Deferribacteraceae in the Tg mice were increased (Figures 4D, 5E,F, Helicobacteraceae: p = 0.0125; Deferribacteraceae: p = 0.09489), while FOS treatment decreased the abundance of Helicobacteraceae and Deferribacteraceae (Figures 4D and 5E,F, Helicobacteraceae: p = 0.1563; Deferribacteraceae: p = 0.2275). At the genus level, compared with WT group, the abundance of Helicobacter was increased (Figure 5G, p = 0.01251), while that of Lactobacillus in the Tg group was decreased (Figure 5H, p = 0.5077). After FOS treatment, the abundance of Helicobacter in the Tg group was decreased (Figure 5G, p = 0.156), while that of Lactobacillus was increased (Figure 5H, p = 0.109). The representative cladogram showed a significant alteration of microbiota in the Tg group. We used LEfSe to identify the taxa that were significantly different between groups. The character-

0.02274), while FOS treatment decreased the abundance of Proteobacteria in the Tg group (Figures 4A and 5A, p = 0.2276). FOS treatment had no influence on WT animals. No statistical difference was observed between the WT group and the WT + FOS group. At the class level, Bacteroidia, Clostridia, and Epsionproteobacteria were the dominant bacteria (Figure 4B). Compared with the WT group, Epsionproteobacteria in the Tg group were increased (Figures 4B and 5B, p = 0.0125), while Actinobacteria was decreased in the Tg group (Figures 4B and 5C, p = 0.1818). After FOS treatment, the abundance of Epsionproteobacteria was decreased (Figures 5B and 6B, p = 0.1563), while that of Actinobacteria was significantly increased in the Tg group (Figures 4B and 5C, p = 0.02638). At the order level, Bacteroidales, Clostridiales, and Campylobacterales were the dominant bacteria (Figure 4C). Compared with the WT group, Campylobacterales were significantly increased in the Tg group (Figures 4C and 5D, p = 0.0125), while FOS treatment decreased the relative abundance of Proteobacteria (Figures 4C D


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Figure 3. Effects of FOS on levels of PSD-95 and synapsin I in Tg mice. Western blot analysis of PSD-95 and synapsin I expression (A); levels were normalized to levels of the internal control (GAPDH). Quantitative analysis of expression of PSD-95 and synapsin I (B); the reference value of the PSD-95/GAPDH or synapsin I/GAPDH was the ratio of the WT group. Error bars indicate SEM; n = 4−6 for each group. Immunohistochemistry of PSD-95 and synapsin I in the hippocampus (C). The arrows indicated positive cells. Magnification 400×. Scale bar = 50 μm. Quantitative analysis of PSD-95 in immunohistochemistry (D). Quantitative analysis of synapsin I in immunohistochemistry (E). *P < 0.05 vs WT group, **P < 0.01 vs WT group, #P < 0.05 vs Tg group.

istics of these comparisons are presented in Figure 4E,F. The variant taxa occupy high abundance at different taxonomic levels. FOS Treatment Increased the Levels of GLP-1 in the Gut and GLP-1R in the Brain of Tg Mice. The level of GLP-1 in the gut was assessed by immunohistochemistry. The GLP-1 level in the Tg group was lower than that in the WT group (P < 0.01, Figure 6A,B). However, the GLP-1 level in FOS-treated

mice was higher than that in the Tg mice (P < 0.01, Figure 6A,B), indicating that FOS treatment could stimulate GLP-1 secretion in the Tg mice. GLP-1R level was determined by immunohistochemistry and Western blot. In immunohistochemistry, the GLP-1R level in the brain was decreased in the Tg mice compared with that in the WT group (Figure 7A,B), whereas FOS treatment increased it (Figure 7A,B). In Western blot, the GLP-1R level in the Tg group was significantly E


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Figure 4. Effects of FOS on composition of the gut microbiota. Relative abundance of phylum-level (A), class-level (B), order-level (C), and family level (D) gut microbial taxa. Taxonomic represents statistical differences among four groups. Differences are represented by the color of the most abundant class. The diameter of each circle’s diameter is proportional to the taxon’s abundance (E). Histogram of the LDA scores for different abundant genera (F). F


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Figure 5. Effects of FOS on different bacterial taxa. On the phylum level (A), the class level (B and C), the order level (D), the family level (E and F), and the genus level-selected major taxa (G and H). Error bars indicate SEM; n = 4−6 for each group. *P < 0.05 vs WT group, **P < 0.01 vs WT group; # P < 0.05 vs Tg group. G


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Figure 6. Effects of FOS on level of colonic GLP-1 in Tg mice. Immunohistochemistry for GLP-1 (A). The arrows indicated positive cells. Magnification 20×. Scale bar = 100 μm. Quantitative analysis of PSD-95 and synapsin I in immunohistochemistry (B). **P < 0.01 vs WT group, #P < 0.05 vs Tg group.

mice. And pathological changes and cognitive deficits occur simultaneously. Congo red staining was used as a reliable indicator of amyloid plaques deposition. Our findings suggested that FOS treatment could reverse the pathological changes in the Tg mice. Furthermore, the Aβ42 level in the FOS-treated group was dramatically decreased compared with the Tg group. C-Jun NH terminal kinase (JNK) is related to the production of Aβ.36,37 JNK regulates the γ-secretase, which mediated cleavage of the C-terminal fragment of APP.38 Inactivation of JNK could decrease the Aβ production and actuate cognitive deficits in the AD mouse.39,40 Our results showed FOS treatment could inhibit activity of JNK in the Tg mice. Taken together, FOS treatment could ameliorate cognitive deficits and Aβ deposition in the Tg mice. Abnormal synaptic plasticity appears as a core feature of AD.41−43 Synaptic plasticity was a form of rapid upregulation of neurotransmission after repetitive stimulation of axonal projections that is considered to be related to memory formation.44−46 The accumulation of plaques could affect synaptic activity,47,48 which was an early pathogenic event in AD. Synapsin I and PSD-95 were an indicator of synaptic plasticity. Synapsin I was a presynaptic protein that responds to neuronal activity. PSD-95 was a common marker of postsynaptic components,49 which was capable of excitatory signaling at postsynaptic levels50 and enhancing synaptic integrity.51

increased (P < 0.05, Figure 7C,D), whereas that of the FOStreated mice was significantly increased level of GLP-1R compared with the Tg group (P < 0.05, Figure 7C,D) indicated that FOS treatment could activate GLP-1/GLP-1R in the Tg mice.

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DISCUSSION FOS, as dietary supplements, play major roles in regulating gut microbiota. In this study, FOS treatment could ameliorate the cognitive impairment and neuropathology change in the Tg mice. Meanwhile, FOS treatment significantly increased the levels of PSD-95 and synapsin I, inhibited the phosphorylated level of JNK, and increased levels of colonic GLP-1 and cerebral GLP-1R, which were associated with the reverse of the altered gut microbial in the Tg mice. Cognitive deficits are the main manifestation of AD. The Tg mouse showed obvious impairment of learning and memory abilities.23,35 Recent studies have indicated that prebiotics fructooligosaccharides from morinda officinalis improved cognitive deficits in rats with AD-like symptoms.11,23 Many behavioral changes in the Tg mice are reversed by FOS treatment, which increases locomotor activity in the OFT, the residence time of the quadrant in the MWM, and the discrimination index in the ORT. Our findings suggested that FOS treatment could effectively alleviate cognitive deficits of Tg H


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Figure 7. Effects of FOS on level of GLP-1R in the hippocampus of Tg mice. Immunohistochemistry for GLP-1R in the hippocampus (A); the arrow indicates GLP-1R-positive cells. Magnification 400×. Scale bar = 50 μm. Quantitative analysis of GLP-1R in immunohistochemistry (B). Western blot analysis of GLP-1R expression (C); levels were normalized to levels of the internal control (GAPDH); quantitative analysis of expression of GLP-1R (D). Reference value of the GLP-1R/GAPDH or synapsin I/GAPDH was the ratio of the WT group. Error bars indicate SEM; n = 4−6 for each group. *P < 0.05 vs WT group, #P < 0.05 vs Tg group.

animal models were altered.7,9 Indeed, probiotics treatment has shown beneficial effects on impairment of synaptic activity and cognitive function.55 Our previous studies demonstrated that probiotics Clostridium butyricum and its metabolites butyrate could improve depression,12 vascular dementia,13 and traumatic brain injury15,56 in animal models. Recently, the prebiotics fructooligosaccharides from Morinda of f icinalis improved memory dysfunction11 and spatial exploration dysfunction in model mice.57 Thus, prebiotics might provide a means to

Accumulating evidence indicates that levels of synapsin I and PSD-95 in AD mice were significantly decreased.43,52 In this study, FOS treatment significantly reversed the decreased level of PSD-95 and synapsin I in the Tg mice, indicating that FOS treatment could prevent the abnormal synaptic plasticity of AD. Alterations of the gut microbiome composition might result in AD.7,8 Gut microbes could influence brain function via the gut− brain axis.6,9,53,54 Accumulating evidence showed a link between gut microbiome and AD.6,9 Gut microbiota in AD patients and I


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Figure 8. Schematic diagram of the mechanism. FOS treatment exerted beneficial effects against AD via regulating the gut microbiota-GLP-1/GLP-1R pathway.

as could inhibit amyloidogenic APP in a mouse model of AD.39 In this study, FOS treatment could increase secretion of GLP-1 and subsequently activate GLP-1R in the brain of Tg mice, inhibit activation of JNK, and diminish Aβ deposit, suggesting anti-AD effect of FOS via activating GLP-1/GLP-1R. Our hypothesis regarding this neuroprotective mechanism of FOS is presented in Figure 8. Further mechanisms need to be explored in the future.

attenuate AD. Our results demonstrated that the gut microbiota composition in the Tg mice were altered, and the effect was reversed after FOS treatment. Proteobacteria was significantly increased in the Tg group, while FOS treatment reversed it on the phylum level. In line with present results, Biagi et al. reported that abundance of Proteobacteria increased in the aged.58 Bauerl et al. revealed that AD pathogenesis in the Tg model mouse could shift the gut microbiota, accompanied by higher Proteobacteria.59 Moreover, Proteobacteria was related to immunological reactions and inflammation, which were related to AD pathogenesis60 and an increased risk of dementia.61 In present study, FOS treatment reversed increase of the abundance of Helicobacteraceae and Desulfovibrionaceae in the Tg mice. Bauerl et al. found the presence of Helicobacteriaceae and higher abundance of Desulfovibrionaceae in the Tg mice at the family level.59 Helicobacteraceae, Desulfovibrionaceae, and Helicobacter were significantly increased in APP/PS1 mice.8 Desulfovibrionaceae had significantly negative correlation with spatial learning and memory and object recognition memory at the family level. In this study, the abundance of Lactobacillus was decreased in the Tg group, while FOS treatment reversed decreased Lactobacillus in the Tg group. Moreover, it has been proposed that gut microbiota alteration in AD will help better elucidate the pharmacology of many agents.62 Indeed, FOS could offer health benefits involved with regulation of the gut microbiota, which can increase the beneficial microbes including Lactobacillus. In addition, Lactobacillus have great effects on the brain−gut axis.20,21 More research is needed to determine the certain bacteria or bacterial activities of FOS on AD. GLP-1 was one of the important mediators at the gut−brain axis20,63 and was mainly secreted by L-cells in the gut. The number of L-cell increased along the longitudinal axis of the gastrointestinal tract.64 The lumen of the colon, hosting a large number of gut microbiota, contains the highest proportion of Lcells.65 Gut microbiota were in direct contact with L-cells. Thus, secretion of GLP-1 was influenced by gut microbiota.24 Lactobacillus treatment could increase secretion of GLP-1.66,67 Probiotics VSL#3 affected gut microbiota and then could affect GLP-1 secretion.68 Recent studies have shown that GLP-1 could bind to its receptor in the brain and affect brain function via the gut−brain axis, such as decreasing the level, aggregation, and accumulation of β-amyloid.27−29,69 Several studies confirm that GLP-1 and several of its analogues, liraglutide and exendin-4, could reduce the Aβ level and amyloid deposition in APP/PS1 mouse.30,70,71 The beneficial effect of GLP-1 is mediated by binding to its receptor. Perry et al. reported that a GLP-1R agonist could reduce the levels of Aβ and APP.70 GLP-1 analogues, GLP-1R agonist, and exendin-4 could inhibit the activity of JNK.72 The inhibition of JNK activation could decrease the Aβ production and nonamyloidogenic APP, as well

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CONCLUSIONS Our results demonstrated that FOS could exert an anti-AD effect in mice, and the involved mechanisms were attributed to the gut microbiota-GLP-1/GLP-1R pathway. Our current study possibly offered an effective strategy of treatment of AD patients.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.8b07313.

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Figure S1 showing effect of FOS on the level of Aβ42 in the brain (PDF)

AUTHOR INFORMATION

ORCID

Jiaming Liu: 0000-0002-0483-3187 Author Contributions #

(J. Sun and S. Liu) These authors equally contributed to this work. Funding

This work was supported by National Natural Science Foundation of China (81871094) and Welfare Technology Applied Research Project of Zhejiang Province (2017C37108). Notes

The authors declare no competing financial interest.

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REFERENCES

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