Article Cite This: J. Agric. Food Chem. 2019, 67, 7684−7693
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Protective Effect of Caffeic Acid against Alzheimer’s Disease Pathogenesis via Modulating Cerebral Insulin Signaling, β‑Amyloid Accumulation, and Synaptic Plasticity in Hyperinsulinemic Rats Wenchang Chang,†,∇ Dawei Huang,‡,∇ Y. Martin Lo,§ Qinqiao Tee,∥ Poling Kuo,∥ James Swibea Wu,⊥ Wenchung Huang,# and Szuchuan Shen*,∥ †
Department of Food Science, National Chiayi University, No. 300, Syuefu Road, Chiayi City 60004, Taiwan Department of Biotechnology and Food Technology, Southern Taiwan University of Science and Technology, No. 1, Nan-Tai Street, Yungkang District, Tainan City 710, Taiwan § Institute for Advanced Study, Shenzhen University, 3688 Nanhai Blvd, Nanshan District, Shenzhen 518060, China ∥ Graduate Program of Nutrition Science, National Taiwan Normal University, No. 162, Sec. 1, Heping East Road, Taipei 10610, Taiwan ⊥ Graduate Institute of Food Science and Technology, National Taiwan University, P.O. Box 23-14, Taipei 10672, Taiwan # Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, No. 261, Wenhua First Road, Guishan District, Taoyuan 33303, Taiwan
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ABSTRACT: This study investigated the alleviative effect of caffeic acid (CA) on Alzheimer’s disease (AD) pathogenesis and associated mechanisms in high-fat (HF) diet-induced hyperinsulinemic rats. The results of a Morris water maze indicated that, by administrating CA (30 mg/kg b.w./day) for 30 weeks, the memory and learning impairments in HF-induced hyperinsulinemic rats were significantly ameliorated. CA also enhanced superoxide dismutase and glutathione free radical scavenger activity in hyperinsulinemic rats. The Western blot data further confirmed that protein expressions of phosphorylatedglycogen synthase kinase 3β (GSK3β) were significantly increased, whereas the expression of phosphorylated-tau protein decreased in the hippocampus of rats administered with CA in comparison with the HF group. Moreover, the expression of amyloid precursor protein (APP) and β-site APP cleaving enzyme were attenuated, subsequently lowering the level of βamyloid 1−42 (Aβ 1−42) in the hippocampus of CA-treated hyperinsulinemic rats. CA also significantly increased the expression of synaptic proteins in HF rats. KEYWORDS: caffeic acid, hyperinsulinemic, Alzheimer’s disease, cerebral carbohydrate metabolism
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impaired glucose tolerance and insulin resistance.10 Studies have indicated that the pathology of brain insulin resistance may be the cause of long-term peripheral insulin resistance, consequently leading to the decrease of insulin concentrations and insulin receptor inactivation in the brain.11 Insulin signaling transduction plays an important role in the occurrence of AD, brain-type diabetes, or Type 3 diabetes.12 Insulin receptors in the brain were found to decrease as age increases.13 Therefore, insulin-related signal transduction may be associated with neurocognitive disorder.13 Glycogen synthase kinase 3 (GSK3), a ubiquitous serine/threonine kinase, is a downstream protein of the insulin signal that plays a key role in the progress of AD.5 Inhibition of GSK3 activation is modulated by AKT, which may be a potential target for Aβ production by tau aggregation and neurodegeneration.5,14 Aβ40 and Aβ42 are common types of Aβ and are produced from the sequential cleavage of amyloid precursor protein
INTRODUCTION With more than 35 million people suffering from Alzheimer’s disease (AD) worldwide, AD to date has become the sixth leading cause of death in the United States and the most common form of dementia, and the disease accounts for 60− 80% of dementia cases.1 AD is characterized as a neurodegenerative disease and is most commonly recognized by continuously worsening dementia symptoms over a number of years. Cognitive-related regions in the brain of AD patients were found to have deposits of neuron plaques and neurofibrillary tangles (NFTs) in extra- and intranerve cells, respectively, which could lead to synaptic dysfunction and neuron death.2,3 Numerous literature has revealed that AD is associated with multiple cellular disorders, including mitochondrial damage, loss of synapses and neurons, amyloid beta (Aβ) formation and deposits, activation of microglia and astrocytes, phosphorylation of tau protein, and neurofibrillary tangles formation.4−7 The diseases share several common abnormalities such as impaired glucose metabolism, increased oxidative stress, insulin resistance, and deposition of amyloidogenic proteins.8 A high-fat (HF) diet may cause weight gain and the pathogenesis of obesity in humans and rodents,9 resulting in © 2019 American Chemical Society
Received: Revised: Accepted: Published: 7684
April 3, 2019 June 14, 2019 June 16, 2019 June 16, 2019 DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry
Figure 1. Morris water maze test’s (A) spatial performance phase and (B) probe trial in hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a, b) are significantly different at p < 0.05. Values were calculated as the mean ± SD for seven rats in each group.
(APP) by β- and γ-secretase. Aβ42 is hydrophobic and liable to assemble into oligomers that may alter the function of mitochondria in synapses, increase oxidative stress, and cause chronic inflammation of the nerve cells and nerve cell apoptosis, eventually leading to cognitive memory impairment.15 HF diet-induced insulin-resistant rats were found in the enhancement of Aβ expression due to the impaired downstream signal of the insulin receptor in the hippocampus, increased β-secretase and γ-secretase activity, and decreased insulin-degrading enzyme (IDE) activity.16,17 Caffeic acid (CA), an antioxidant abundant in nature, is an analogue of ferulic acid yet has more potent pharmacological activities, including antioxidative, anti-inflammatory, anticancer, antiviral, analgesic, and immunomodulatory effects.18,19 The neuroprotective mechanism of CA has been investigated against Aβ-induced neurotoxicity through inhibition of calcium influx and tau phosphorylation, which otherwise is found upregulated in neurodegenerative disorders.20 However, the in vivo efficacy of CA against HF diet-induced cerebral insulin resistance to mediating neurodegeneration has not yet been reported. Therefore, this study aimed to elucidate the protective effect of CA against pathogenesis of AD in HFinduced hyperinsulinemic rats.
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orally administered 30 mg/kg body weight CA once a day for 30 weeks (HF+CA group). The rats were sacrificed at the end of the experiment. The brain tissue of the rats was plucked for further biochemical measurements and Western blot analysis. Morris Water Maze Test. The Morris water maze test was conducted prior to when the rats were sacrificed after 30 weeks of the animal experiment. The method was adapted from Morris (1984).21 Briefly, rats were subjected to one session of four trials per day for four consecutive days (0−4th day). During each trial, the rat was placed in each quadrant to eliminate quadrant effects. On day 5 (probe day), 24 h after the previous training, the escape platform was removed before conducting the spatial probe trials. The cutoff time for animals to swim was set to 60 s before the end of the session. Time of passing the removed escape platform was measured to evaluate the capability of spatial memory in hyperinsulinemic rats. Brain Homogenate. The preparation of rat brain homogenate followed a method established by our previous study.22 Biochemical Measurements. ELISA kits for rat β-amyloid 1−42 were purchased from Anaspec Laboratories (CA, USA). ELISA kits for rat catalase and superoxide dismutase (SOD) were purchased from Cayman Chemical Company (MI, USA). Analyses were performed following the supplier’s protocols. Western Blot Analysis. The performance of Western bolt analysis was adapted from Chang et al. with minor modifications.22 Briefly, aliquots of 50 μg of protein supernatants were separated by SDS-polyacrylamide gel electrophoresis and then transferred to a polyvinylidene difluoride membrane. The membrane was subsequently probed with anti-GSK3β, antiphospho-GSK3β, and anti-Tau (Tau46) antibodies (Cell Signaling Technology, Danvers, MA, USA), anti-BACE, antidrebrin, antiphospho-Tau (Ser404), anti-PSD95, and anti-synaptophysin antibodies (Abcam Company, Cambridge, England), antiphospho-Tau (Ser181), and antiphospho-Tau (Ser396) antibody (Gene Tex, Irvine, CA, USA) overnight at 4 °C. The mouse monoclonal β-actin antibody (Gene Tex) was used as an internal control. After washing, the membrane was incubated with horseradish peroxidase-linked antimouse IgG or antirabbit IgG secondary antibody and then revealed using chemiluminescence detection reagent (Millipore). The blot images were captured and the optical density of trace quantity for each band was measured using ImageJ software. Statistical Analysis. Data are presented as the mean ± standard deviation (SD). Groups were compared by one-way ANOVA and Duncan’s new multiple range tests to compare all groups to each other. A P value less than 0.05 was considered statistically significant.
MATERIALS AND METHODS
Chemicals. Caffeic acid (CA) and pioglitazone hydrochloride (PIO) were purchased from Sigma (St. Louis, MO, USA). All of the chemicals used in this study were of analytical grade. Animal Experiment. All experimental protocols in this study were approved by the Institutional Animal Care and Use Committee of the National Taiwan Normal University (approval no. 99036). Animals were handled in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. Briefly, male Sprague−Dawley rats (8-weeks old) were individually housed under a 12:12 h light/dark cycle and controlled temperature, with free access to commercial rat chow (Young Li Trading Co., Ltd., Taipei, Taiwan) and water for 1 week to achieve a body weight of approximately 250 g. The rats were then divided into a control group and three experimental groups (8 rats in each group). The first group rats were fed a commercial rat chow diet for 30 weeks (normal group). The second group rats were fed a high-fat diet (60% calories from fat, Young Li Trading Co., Ltd., Taipei, Taiwan) for 30 weeks (HF group). The third group rats were fed a high-fat diet and orally administered 30 mg/kg body weight PIO once a day for 30 weeks (HF+PIO group). The fourth group rats were fed a HF and daily 7685
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry
Figure 2. Superoxide dismutase (SOD) activity, catalase activity, and glutathione contents of the hippocampus and the cortex in hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a, b) are significantly different at p < 0.05. Values were calculated as the mean ± SD for three rats in each group.
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Effect of CA on Cerebral Antioxidant Substance in Hyperinsulinemic Rats. Figure 2 shows the SOD, catalase activities, and glutathione contents of the hippocampus and cortex in hyperinsulinemic rats treated with CA. Significant reductions of SOD and catalase activities were observed in the HF group as compared with the normal group from the hippocampus and cortex (Figure 2A, B, D, and E). Administration of CA caused a 36.6% and 22.8% increase of SOD activities and a 13.3% and 12.8% decrease of catalase activities in the hippocampus and cortex, respectively, as compared with the HF rats (Figure 2A, B, D, and E). Hyperinsulinemic rats administered with CA remarkably
RESULTS
Effect of CA on Memory in Hyperinsulinemic Rats. The Morris water maze test was employed to assess memory decline in HF-induced hyperinsulinemic rats orally administered with CA. It was found that the escape latency time in spatial performance test for rats in the HF+CA group were significantly lower than that in the HF group (Figure 1). Administration of CA for 30 weeks increased the removed platform passing times of the Morris water maze test’s probe trial in comparison with the HF group. The results indicate that CA may ameliorate the capability of spatial memory in HF-induced hyperinsulinemic rats. 7686
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry
Figure 3. Amyloid beta degradation and formation-related proteins in the hippocampus and cortex of hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a−c) are significantly different at p < 0.05. The expression of protein data was calculated as the mean ± SD for three rats in each group. Values were calculated as the mean ± SD for three rats in each group.
increased by 167% of the hippocampus in the HF group compared with the normal group, which was reversed by PIO or CA, leading to a 63.8% and 62.9% decrease, respectively (Figure 4). Effect of CA on Cerebral Insulin TransductionRelated Proteins Expression in High-Fat Diet Rats. The cerebral insulin transduction-related protein expression of the hippocampus and cortex was also studied in hyperinsulinemic rats treated with CA (Figure 5). Hippocampal inactive GSK3β expression levels in the HF diet group were significantly downregulated by 52.8% compared to the ND group (Figure 5A). The respective hippocampal inactive GSK3β expression level in the HF+PIO and HF+CA groups were up-regulated by 172% and 38.3% compared to those of the HF group (Figure 5A). However, the expression levels of inactive GSK3β from cortex in insulin signaling were not different among the tested animals (Figure 5B).
reduced the GSSG/total GSH ratio by 40.6% in their cortex (Figure 2F). Effect of CA on Amyloid Beta Degradation from Hippocampus and Cortex in High-Fat Diet Rats. Numerous literature reports have shown that polyphenol exerts beneficial effects on AD, an age-related neurodegenerative condition that in some cases is also combined with metabolic disorders such as type-2 diabetes mellitus and obesity.23−25 In the present study, we investigated the effect of CA on β-amyloid degradation-related proteins and contents of the hippocampus and cortex in hyperinsulinemic rats. βSecretase (BACE) expression levels in the hippocampus and cortex of HF+CA group rats were down-regulated by 26.0% and 31.6%, respectively, compared to HF group rats (Figure 3A and C). APP protein expression in the hippocampus and cortex was increased by the administration with HF, and the increment could be offset by CA (37.3% and 36.0%, respectively) (Figure 3B and D). β-Amyloid content was 7687
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry
Figure 4. Amyloid beta contents in the hippocampus and cortex of hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a, b) are significantly different at p < 0.05. The expression of protein data was calculated as the mean ± SD for three rats in each group. Values were calculated as the mean ± SD for three rats in each group.
Figure 5. Expression of insulin transduction-related proteins in the hippocampus and cortex of hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a−c) are significantly different at p < 0.05. The expression of protein data was calculated as the mean ± SD for three rats in each group.
Effect of CA on Cerebral Phosphorylated Tau Proteins Expression in Hyperinsulinemic Rats. The cognitive decline in neurodegenerative diseases is known to correlate with deposits of hyperphosphorylated tau, which can lead to abnormal folding, fragmentation, aggregation, and the development of deposits known as neurofibrillary tangles (NFTs).26,27 Figure 6 shows the cerebral phosphorylated tau protein expression in hyperinsulinemic rats treated with CA. Administration of HF caused a 60.61% increase in cortical pTau (Thr181) expression, and the increment could be reduced by 38.11% and 36.71% via treatment with PIO and CA, respectively (Figure 6F). No significant differences were observed in the expression of p-Tau Ser396 and p-Tau Ser404 proteins of the hippocampus and cortex among all tested animals (Figure 6B, D, and E). Effect of CA on Cerebral Neuroplasticity-Related Proteins Expression in Hyperinsulinemic Rats. Figure 7 showed the cerebral neuroplasticity-related proteins expression
of the hippocampus and cortex in hyperinsulinemic rats orally administered with CA. Synaptophysin expression in the cerebral cortex, as well as drebrin expression in the hippocampus and cortex, was increased in hyperinsulinemic rats administrated with CA for 30 weeks (Figure 7).
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DISCUSSION Epidemiological studies have shown that diabetes, particularly type-2 diabetes mellitus, significantly increases 2−3-fold the risk to develop AD compared to healthy adults.8 Dietary fat composition has been demonstrated as crucial in the prevention and treatment of cardiovascular diseases and diabetes, conditions that have been implicated as risk factors for dementia.28 Long-term high-fat and high-sugar diets were verified to be involved in the injury of hippocampal function, leading to declining performance of rats in water maze tests.29 The net bioavailability accounted for 19.5% of the perfused CA in the small intestine of rats.30 In this study, CA was found to 7688
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
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Journal of Agricultural and Food Chemistry
Figure 6. Cerebral proteins expression of phosphorylated tau in the hippocampus and cortex of hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.).
respiration, leading to Aβ-induced oxidative stress involved in the pathogenesis of AD.31 The results of this study showed that administration of CA caused a significant amelioration in SOD activities but no significant improvement in catalase activities of hippocampus in hyperinsulinemic rats (Figure 2A and B). Attenuation of SOD and catalase activities may produce excess H2O2 and cause oxidation of GSH into GSSG, leading to the enhancement of the GSSG/total GSH ratio in HF rats. Treatment of CA may remarkably decrease the GSSG/total GSH ratio of cortex in hyperinsulinemic rats
significantly reduce the escape latency time in the spatial performance phase and enhance the passing times in the spatial probe phase, indicating that an ameliorative effect in the learning and memory ability of high-fat feeding-induced hyperinsulinemia rats is exhibited (Figure 1). Cognitive disorder of AD was proven to be associated with oxidation damage due to the imbalance of oxidation and antioxidation in animal and human models. Proteolytically produced from APP, Aβ may cause manganese superoxide dismutase (MnSOD) activity and decrease mitochondrial 7689
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry
Figure 7. Neuroplasticity-related proteins expression in the hippocampus and cortex of hyperinsulinemic rats treated with caffeic acid for 30 weeks. ND, normal diet; HF, high-fat diet (HF) (60% fat); HF+PIO, HF (60% fat) + pioglitazone (30 mg/kg B.W.); HF+CA, HF (60% fat) + caffeic acid (30 mg/kg B.W.). Different letters (a−c) are significantly different at p < 0.05. The expression of protein data was calculated as the mean ± SD for three rats in each group.
increasing BACE expression and APP formation, causing nerve cell toxicity through Aβ accumulation.33 Aβ accumulation has been recognized as an inducer for GSK3β activation that resulted in tau phosphorylation.7 In the present study, CA exhibited the protective effect in nerve cells due to a decrease of Aβ accumulation by drastically decreasing the expressions of BACE and APP in the cerebral hippocampus of hyperinsulinemic rats (Figure 3A, B and Figure 4). The tauopathies are recognized as neurodegenerative disorders characterized by hyperphosphorylation and aggrega-
(Figure 2 F). Overexpression of mitochondrial superoxide dismutase (SOD-2) was proven to decrease hippocampal superoxide and prevent AD-related memory impairments in a mouse model of AD.32 We speculated that CA prevented oxidative damage of nerve cell and AD-related memory impairments via ameliorating impaired SOD activity and retaining GSH content in high-fat feeding-induced hyperinsulinemia rats. Aβ formation resulted from the sequential cleavage of APP by BACE and γ-secretase.6,15 Oxidative stress played a role in 7690
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
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Journal of Agricultural and Food Chemistry
as a marker of synaptic content.44 PSD-95, an amino-acid postsynaptic protein, was reported to be necessary for the synaptic plasticity.42 Drebrin, a 649-amino acid protein, is involved in dendritic spine morphogenesis.45 All of these synaptic proteins were found to be reduced significantly in AD and minimal cognitive impairment.42,46 Based on our findings, CA may enhance synaptophysin expression in cerebral cortex (Figure 7D) and ameliorate drebrin expression in cerebral hippocampus and cortex of hyperinsulinemic rats (Figure 7C and F). Additionally, CA effectively protected the synaptic plasticity and retained normal function of neural signaling by synaptic proteins that consequently improved BDNF expression. The administration of CA may ameliorate SOD activity and enhance GSH content to protect neuron cells from the attack of oxidative stress in the hippocampus and cortex of hyperinsulinemic rats. CA also modulated IDE and decreased BACE expression to decline Aβ accumulation, causing neuron cell toxicity. Moreover, CA contributed to the activation of AKT that inhibited GSK3β activity and upregulated BDNF expression, leading to the alleviation of Aβ accumulation and neuroprotection in cerebral neuron cells. However, promoting BDNF expression may promote the synthesis of synaptic proteins, subsequently protecting the synaptic plasticity. We propose that CA may ameliorate memory function via enhancing cerebral insulin signaling, alleviating Aβ production and retaining synaptic plasticity in HF-induced hyperinsulinemic rats. Therefore, CA may possess benefits to prevent the progression of AD in diabetes patients.
tion of the microtubule-associated protein tau, resulting in the accumulation of neurotoxic neurofibrillary tangles (NFTs), microtubule disorganization, and impaired transport along axonal microtubules in the brain.4,34 Protein phosphatase 2A (PP2A) is responsible for degradation of abnormal tau phosphorylation, and the activities were decreased to cause tau hyperphosphorylation in STZ-induced diabetic mice with AD.35 CA may significantly ameliorate excess expression of pTau (Thr181) in the cerebral cortex of hyperinsulinemia rats (Figure 6F). Moreover, mice fed a high-fat or high-cholesterol diet were verified to impair downstream proteins of brain insulin/IGF signaling such as IRS-1 and p-AKT and to cause an enhancement of GSK3β activation that in turn resulted in tau hyperphosphorylation. Further, 46 Akt is a predominant mediator to prohibit GSK3 activation via phosphorylation of a regulatory serine in either of the two isoforms of GSK3, namely, serine-9 in GSK3β or serine-21 in GSK3α.36,37 Activation of GSK3 can cause hyperphosphorylation in serine and threonine residues of tau, and the GSK3 activity contributes both to Aβ production and Aβ-mediated neuronal death that is related in the pathogenesis of AD.5,37 While administration of CA has been reported to remarkably enhance IR and AKT activity,22 it was also found to inhibit GSK3 activation via increasing p-GSK3β (Ser9) expression in the hippocampus of hyperinsulinemic rats (Figure 5A). GSK3 has been demonstrated to play an important role in tau phosphorylation in the brain.6 Therefore, it could be postulated that CA inhibiting GSK3 activity for amelioration on tau hyperphosphorylation may prevent NFTs formation that causes neurofibrillary pathology. Brain-derived neurotrophic factor (BDNF), a widely distributed neurotrophin in the central nervous system, is necessary for neuronal survival and synaptic plasticity.38,39 Most clinical evidence indicates that reduced BDNF expression in brains is related in the pathogenesis of AD. 38,40 Tropomyosin-related kinase B (TrkB), a receptor for BDNF, is activated by the bound of BDNF for synaptic plasticity, neuronal survival, and differentiation. The Trk/BDNF pathway is a pivotal mechanism for the pathogenesis of AD due mainly to the expressions of TrkB and BDNF; both have been found to reduce in the brain of patients with AD.41 The hippocampus and cortex in the brain possess high levels of BDNF expression, which is reduced to impair cerebral neuroplasticity and nerve development, causing the damage of learning and memory ability. BDNF contributed to a neuroprotective effect against the attack of Aβ via activating the PI3K/AKT pathway for inhibition of GSK3β associated with tau hyperphosphorylation.36 In the current study, CA significantly enhanced BDNF expression in the hippocampus and cortex by 50.5% and 88.0%, respectively, of hyperinsulinemic rats (data not shown). It was made clear that CA may activate the PI3K/AKT pathway to inhibit GSK3β activity and upregulate BDNF expression, resulting in a decrease of Aβ production and the protective effect in cerebral nerve cells. Synaptic loss is association with neuronal loss and synaptic degeneration while being recognized as a major neuropathological abnormality in AD.42 Liao et al. reported that BDNF increases the synthesis of a wide variety of synaptic proteins to enhance the translational capacity of synapse.43 Synaptic proteins such as synaptophysin, postsynaptic density protein 95 (PSD-95), and drebrin play a role in the pathogenesis of central nervous system disorders.42 Synaptophysin is a presynaptic vesicle-specific protein that can be used
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel.: +886-2-77341437. Fax: +8862-23639635. ORCID
Szuchuan Shen: 0000-0001-9005-0455 Author Contributions ∇
These authors have contributed equally to this work.
Funding
The authors thank the National Science Council, Taiwan, for financially supporting this research (NSC 101-2320-B-003004-MY3 and MOST 104-2320-B-003-003-MY3). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank the Academic Paper Editing Clinic, NTNU, for assistance with editing this article. REFERENCES
(1) Alzheimer’s Association. 2016 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2016, 12 (4), 459−509. (2) Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297, 353−356. (3) Mattson, M. P. Pathways towards and away from Alzheimer’s disease. Nature 2004, 430, 631−639. (4) Alavi-Naini, S. M.; Soussi-Yanicostas, N. Tau Hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid. Med. Cell Longev. 2015, 2015, 1−17. (5) Hernandez, F.; Lucas, J. J.; Avila, J. GSK3 and tau: two convergence pointsin Alzheimer’s disease. J. Alzheimer’s Dis. 2012, 33, S141−S144. 7691
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry (6) Jouanne, M.; Rault, S.; Voisin-Chiret, A. S. Tau protein aggregation in Alzheimer’s disease: An attractive target for the development of novel therapeutic agents. Eur. J. Med. Chem. 2017, 139, 153−167. (7) Reddy, P. H. Amyloid beta-induced glycogen synthase kinase 3β phosphorylated vdac1 in alzheimer’s disease: implications for synaptic dysfunction and neuronal damage. Biochim. Biophys. Acta, Mol. Basis Dis. 2013, 1832, 1913−1921. (8) Correia, S. C.; Santos, R. X.; Carvalho, C.; Cardoso, S.; Candeias, E.; Santos, M. S.; Oliveira, C. R.; Moreira, P. I. Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer’s disease and diabetes interrelation. Brain Res. 2012, 1441, 64−78. (9) Buettner, R.; Scholmerich, J.; Bollheimer, L. C. High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity 2007, 15, 798−808. (10) Riccardi, G.; Giacco, R.; Rivellese, A. A. Dietary fat, insulin sensitivity and the metabolic syndrome. Clin. Nutr. 2004, 23, 447− 456. (11) de la Monte, S. M.; Longato, L.; Tong, M.; Wands, J. R. Insulin resistance and neurodegeneration: roles of obesity, type-2 diabetes mellitus and non-alcoholic steatohepatitis. Curr. Opin. Investig. Drugs. 2009, 10 (10), 1049−1060. (12) Steen, E.; Terry, B. M.; Rivera, E. J.; Cannon, J. L.; Neely, T. R.; Tavares, R.; Xu, X. J.; Wands, J. R.; de la Monte, S. M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease - is this type 3 diabetes? JAD 2005, 7, 63−80. (13) Chung, Y. H.; Shin, C. M.; Joo, K. M.; Kim, M. J.; Cha, C. I. Region-specific alterations in insulin-like growth factor receptor type I in the cerebral cortex and hippocampus of aged rats. Brain Res. 2002, 946, 307−313. (14) Lei, P.; Ayton, S.; Bush, A. I.; Adlard, P. A. GSK-3 in neurodegenerative diseases. Int. J. Alzheimer's Dis. 2011, 2011, 1−9. (15) Gunther, E. C.; Strittmatter, S. M. Beta-amyloid oligomers and cellular prion protein in Alzheimer’s disease. J. Mol. Med. (Heidelberg, Ger.) 2010, 88, 331−338. (16) Ho, L.; Qin, W.; Pompl, P. N.; Xiang, Z.; Wang, J.; Zhao, Z.; Peng, Y.; Cambareri, G.; Rocher, A.; Mobbs, C. V.; Hof, P. R.; Pasinetti, G. M. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J. 2004, 18, 902−904. (17) Son, S. M.; Song, H.; Byun, J.; Park, K. S.; Jang, H. C.; Park, Y. J.; Mook-Jung, I. Altered app processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway. Diabetes 2012, 61, 3126− 3138. (18) Chao, X.; He, X.; Yang, Y.; Zhou, X.; Jin, M.; Liu, S.; Cheng, Z.; Liu, P.; Wang, Y.; Yu, J.; Tan, Y.; Huang, Y.; Qin, J.; Rapposelli, S.; Pi, R. Design, synthesis and pharmacological evaluation of novel tacrinecaffeic acid hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg. Med. Chem. Lett. 2012, 22, 6498−6502. (19) Khan, K. A.; Kumar, N.; Nayak, P. G.; Nampoothiri, M.; Shenoy, R. R.; Krishnadas, N.; Rao, C. M.; Mudgal, J. Impact of caffeic acid on aluminium chloride-induced dementia in rats. J. Pharm. Pharmacol. 2013, 65, 1745−1752. (20) Sul, D.; Kim, H. S.; Lee, D.; Joo, S. S.; Hwang, K. W.; Park, S. Y. Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation. Life Sci. 2009, 84, 257−262. (21) Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 1984, 11, 47− 60. (22) Chang, W. C.; Kuo, P. L.; Chen, C. W.; Wu, J. S. B.; Shen, S. C. Caffeic acid improvesmemory impairment and brain glucose metabolismvia ameliorating cerebral insulin and leptin signaling pathways in high-fat diet-induced hyperinsulinemic rats. Food Res. Int. 2015, 77, 24−33.
(23) Baur, J. A.; Pearson, K. J.; Price, N. L.; Jamieson, H. A.; Lerin, C.; Kalra, A.; Prabhu, V. V.; Allard, J. S.; Lopez-Lluch, G.; Lewis, K.; Pistell, P. J.; Poosala, S.; Becker, K. G.; Boss, O.; Gwinn, D.; Wang, M.; Ramaswamy, S.; Fishbein, K. W.; Spencer, R. G.; Lakatta, E. G.; Le Couteur, D.; Shaw, R. J.; Navas, P.; Puigserver, P.; Ingram, D. K.; de Cabo, R.; Sinclair, D. A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444, 337−342. (24) Lagouge, M.; Argmann, C.; Gerhart-Hines, Z.; Meziane, H.; Lerin, C.; Daussin, F.; Messadeq, N.; Milne, J.; Lambert, P.; Elliott, P.; Geny, B.; Laakso, M.; Puigserver, P.; Auwerx, J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006, 127, 1109−1122. (25) Pasinetti, G. M.; Wang, J.; Ho, L.; Zhao, W.; Dubner, L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim. Biophys. Acta, Mol. Basis Dis. 2015, 1852, 1202−1208. (26) Alonso, A. D.; Zaidi, T.; Novak, M.; Grundke-Iqbal, I.; Iqbal, K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 6923−6928. (27) Murray, M. E.; Lowe, V. J.; Graff-Radford, N. R.; Liesinger, A. M.; Cannon, A.; Przybelski, S. A.; Rawal, B.; Parisi, J. E.; Petersen, R. C.; Kantarci, K.; Ross, O. A.; Duara, R.; Knopman, D. S.; Jack, C. R., Jr.; Dickson, D. W. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’sdisease spectrum. Brain 2015, 138, 1370−1381. (28) Morris, M. C.; Tangney, C. C. Dietary fat composition and dementia risk. Neurobiol. Aging 2014, 35, S59−S64. (29) Kanoski, S. E.; Zhang, Y.; Zheng, W.; Davidson, T. L. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J. Alzheimer's Dis. 2010, 21, 207−219. (30) Lafay, S.; Morand, C.; Manach, C.; Besson, C.; Scalbert, A. Absorption and metabolism of caffeic acid and chlorogenic acid in the small intestine of rats. Br. J. Nutr. 2006, 96, 39−46. (31) Anantharaman, M.; Tangpong, J.; Keller, J. N.; Murphy, M. P.; Markesbery, W. R.; Kiningham, K. K.; St. Clair, D. K. Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am. J. Pathol. 2006, 168, 1608−1618. (32) Massaad, C. A.; Pautler, R. G.; Klann, E. Mitochondrial superoxide: a key player in Alzheimer’s disease. Aging 2009, 1, 758− 761. (33) Tamagno, E.; Bardini, P.; Obbili, A.; Vitali, A.; Borghi, R.; Zaccheo, D.; Pronzato, M. A.; Danni, O.; Smith, M. A.; Perry, G.; Tabaton, M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol. Dis. 2002, 10, 279−288. (34) Avila, J.; Leon-Espinosa, G.; Garcia, E.; Garcia-Escudero, V.; Hernandez, F.; Defelipe, J. Tau phosphorylation by GSK3 in different conditions. Int. J. Alzheimer's Dis. 2012, 2012, 1−7. (35) Jolivalt, C. G.; Lee, C. A.; Beiswenger, K. K.; Smith, J. L.; Orlov, M.; Torrance, M. A.; Masliah, E. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J. Neurosci. Res. 2008, 86, 3265−3274. (36) Bhat, N. R.; Thirumangalakudi, L. Increased Tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. J. Alzheimer's Dis. 2013, 36, 781−789. (37) Jope, R. S.; Yuskaitis, C. J.; Beurel, E. Glycogen synthase kinase3 (GSK3): inflammation, diseases, and therapeutics. Neurochem. Res. 2007, 32, 577−595. (38) Jiao, S. S.; Shen, L. L.; Zhu, C.; Bu, X. L.; Liu, Y. H.; Liu, C. H.; Yao, X. Q.; Zhang, L. L.; Zhou, H. D.; Walker, D. G.; Tan, J.; Götz, J.; Zhou, X. F.; Wang, Y. J. Brain-derived neurotrophic factor protects against tau-relatedneurodegeneration of Alzheimer’s disease. Transl. Psychiatry 2016, 6, No. e907. (39) Schindowski, K.; Belarbi, K.; Buee, L. Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes, Brain Behav. 2008, 7, 43−56. 7692
DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
Article
Journal of Agricultural and Food Chemistry (40) Sampaio, T. B.; Savall, A. S.; Gutierrez, M. E. Z.; Pinton, S. Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: implications for pathogenesis and therapy. Neural Regener. Res. 2017, 12, 549−557. (41) Zhang, F.; Kang, Z.; Li, W.; Xiao, Z.; Zhou, X. Roles of brainderived neurotrophic factor/tropomyosin-related kinase B (BDNF/ TrkB) signalling in Alzheimer’s disease. J. Clin. Neurosci. 2012, 19, 946−949. (42) Sinclair, L. I.; Tayler, H. M.; Love, S. Synaptic protein levels altered in vascular dementia. Neuropathol. Appl. Neurobiol. 2015, 41, 533−543. (43) Liao, L.; Pilotte, J.; Xu, T.; Wong, C. C.; Edelman, G. M.; Vanderklish, P.; Yates, J. R. BDNF induces widespread changes in synaptic protein content and up-regulates components of the translation machinery: an analysis using high-throughput proteomics. J. Proteome Res. 2007, 6, 1059−1071. (44) Wiedenmann, B.; Franke, W. W. Identification and localizationof synaptophysin, an integral membrane glycoproteinof Mr 38,000 characteristic of presynaptic vesicles. Cell 1985, 41, 1017− 1028. (45) Counts, S. E.; He, B.; Nadeem, M.; Wuu, J.; Scheff, S. W.; Mufson, E. J. Hippocampal drebrin loss in mild cognitive impairment. Neurodegener. Dis. 2012, 10, 216−219. (46) Sze, C.; Bi, H.; Kleinschmidt-DeMasters, B.; Filley, C.; Martin, L. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J. Neurol. Sci. 2000, 175, 81−90.
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DOI: 10.1021/acs.jafc.9b02078 J. Agric. Food Chem. 2019, 67, 7684−7693
