The Effects of Astilbin on Cognitive Impairments in a Transgenic Mouse Model of Alzheimer’s Disease
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Bioflavonoids are being utilised as neuroprotectants in the treatment of various neurological disorders, including Alzheimer’s disease (AD). Astilbin, a bioflavanoid, has been reported to have potent neuroprotective effects, but its preventive effects on amyloid-β (Aβ)-induced, Alzheimer’s disease-related, cognitive impairment, and the underlying mechanisms of these effects have not been well characterised. Five-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group and two astilbin (either 20 or 40 mg/kg per day, intraperitoneally) groups. After 8 weeks of treatment, we observed beneficial effects of astilbin (40 mg/kg per day), including lessening learning and memory deficits and reducing plaque burden and Aβ levels. Furthermore, the expressions of both the cAMP responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly increased and the disturbance of AKT/GSK-3β signalling pathway was markedly ameliorated in the hippocampus of astilbin-treated (40 mg/kg per day) group. Our data suggest that astilbin might be a potential therapeutic agent against AD.
KeywordsAstilbin APPswe/PS1dE9 mice Cognitive ability CREB/BDNF pathway
Brain-derived neurotrophic factor
CAMP responsive element-binding protein
The Ras-mitogen-activated protein kinase
Glycogen synthase kinase-3β
Phosphatidylinositol 3 kinase/protein kinase B
The cAMP/protein kinase A
Total antioxidant capability
Alzheimer’s disease (AD) is a degenerative neurological disease that is characterised by progressive cognitive dysfunction. The formation of extracellular deposits of amyloid-β (Aβ) peptide, leading to the formation of neuritic plaques and neurofibrillary tangles in the cortex and hippocampus, is a prominent pathological feature of AD (Selkoe 2001; Yamada and Nabeshima 2000). Synaptic loss is another characteristic feature of the condition and probably the best correlate of the cognitive decline that develops progressively in AD patients (Terry et al. 1991). The deposition of Aβ in brain areas involved in cognitive functions is assumed to initiate an array of molecular and cellular cascades that lead to synaptic dysfunction (Walsh and Selkoe 2004).
Many plant species containing flavonoids have been widely used in traditional medicine. Recent epidemiological and dietary interventional studies, both in humans and animals, suggest that these flavonoids prevent and delay neurodegeneration, especially in aged population and cognitive dysfunction (Schroeter et al. 2002). Astilbin (AST), an active flavonoid compound is isolated from the rhizome of Smilax china L. (Smilaceae) which is widely used in the traditional Chinese medical treatment. Modern pharmacological researches indicate that astilbin has broad pharmacological functions which may modulate numerous pathways, such as antioxidant, scavenging-free radicals, anti-inflammatory and so on, similarly to some of other flavonoids (Harada et al. 2011; Moulari et al. 2006; Naqinezhad et al. 2012; Petacci et al. 2010). Astibin can be detected in the brain after i.p. administration by a high-performance capillary electrophoresis (HPCE) method in this present study (data not shown), suggesting that astilbin can traverse the blood brain barrier. Recent studies have shown that AST activated the brain-derived neurotrophic factor (BDNF) signalling pathway and improved depressive-like behaviours (Lv et al. 2014). BDNF can promote neuronal survival, neurite outgrowth and synaptic plasticity (Huang and Reichardt 2001; Yoshii and Constantine-Paton 2010) and play a crucial role in memory formation and maintenance (Minichiello 2009; Zhang et al. 2012). It has been demonstrated that the BDNF expression level is severely reduced in the hippocampus and some cortical areas in Alzheimer’s disease (Ferrer et al. 1999; Phillips et al. 1991) and that BDNF administration displayed extension of therapeutic benefits on the degenerating hippocampus in several rodent and primate models of AD (Nagahara et al. 2009). Flavonoids have also been reported to upregulate phosphorylation of cAMP response element-binding protein (CREB)/BDNF pathway and improve spatial memory (Li et al. 2009; Matsuzaki et al. 2006). Activation of transcription factor CREB and the subsequent induction of plasticity-enhancing genes such as BDNF have been considered as an underlying mechanism for neuroplasticity (Pittenger and Duman 2008). In this study, the effect of astilbin consumption on the improvement of memory loss, Aβ burden and CREB/BDNF signal pathway was analysed in the APPswe/PS1dE9 transgenic mouse model of Alzheimer’s disease.
Materials and Methods
APPswe/PS1dE9 mice (C57/BL) used in this study was generated as previously described (Wang et al. 2014a; b). Mice express a mouse–human hybrid transgene containing the extracellular and intracellular regions of the mouse sequence and a human sequence within the Aβ domain with Swedish mutations (K594 N/M595L), and express the human presenilin-1 deleted exon-9. Protocols were conducted according to the University Policies on the Use and Care of Animals and were approved by the Institutional Animal Experiment Committee of Henan University of Science and Technology, China.
Group and Treatment
Five-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to four groups (each n = 14): low-dose astilbin group (20 mg kg−1 d−1; i.p. injection), high-dose astilbin group (40 mg kg−1 d−1; i.p. injection), Aricept (2.5 mg kg−1 d−1; oral administration) and vehicle-treated group (DMSO; i.p. injection) for 8 weeks. Non-transgenic littermates were treated with DMSO via i.p. injection in similar manner and concentration as wild type (n = 14). Each group included seven males and seven females. Astilbin (>98 %, molecular weight of 450.40) was purchased from Bellancom Chemistry (U.S.A.) and was dissolved in dimethylsulfoxide (DMSO) as stock solutions. The stock solutions were diluted to the final concentrations with normal saline before application and the final concentration of DMSO did not exceed 0.1 %. The dose of astilbin was selected based on other experimental studies (Diao et al. 2014; Ding et al. 2014; Lv et al. 2014). All these i.p. agents were administered to the mice in a volume of 0.1 mL/10 g/day. The administered dose of Aricept, an inhibitor of acetyl-cholinesterase, was calculated from the weight of the mice to be equivalent to the human dose. Upon conversion of animal dose to the equivalent human dose [human dose (mg/kg) = mouse dose (mg/kg) × (3/37)] (Reagan-Shaw et al. 2008), a dose of 0.2 mg kg−1 d−1Aricept in humans corresponded to 2.5 mg kg−1 d−1 in mice.
Novel Object Recognition Test
The test procedure consisted of three sessions: habituation, training and retention. Each mouse was habituated to the box (30 × 30 × 35 cm), with 10 min of exploration in the absence of objects for 3 days (habituation session). During the training session, two objects were placed at the back corner of the box. A mouse was then placed in the box and the total time spent exploring the two objects (blue wooden cubes of size 3 cm) was recorded for 10 min. During the retention session, the mice were placed back in the same box 24 h after the training session, in which one of the familiar objects used during the training was replaced with a novel object (a yellow wooden cylinder of diameter 3 cm and height 3 cm). The animals were then allowed to explore freely for 5 min, the exploration time for the familiar or the new object during the test phase was recorded. The exploration time for the familiar (T F ) or the new object (T N ) during the test phase was videotaped and analysed using the Noldus Ethovision XT software (Noldus Information Technology, Wageningen, The Netherlands). Memory was defined by the recognition index (RI) for the novel object as the following formula: RI = T N / (T N + T F ) × 100 %. To control for odour cues, the OF arena and the objects were thoroughly cleaned with 10 % odourless soap, dried, and ventilated for a few minutes between mice (Bevins and Besheer 2006; Takamura et al. 2011).
Morris Water Maze
Spatial learning and memory was tested using the Morris water maze, performed after the end of novel object recognition test. The protocol for the Morris water maze test was modified from previously reported methods (Laczo et al. 2009; Liang et al. 1994). Briefly, the apparatus included a pool with a diameter of 100 cm that was filled with opaque water at approximately 22 ± 1 °C. An escape platform (15 cm in diameter) was placed 0.5 cm below the water surface. Geometric objects with contrasting colours were set at the remote ends of the water tank as references. Room temperature was constant, and the lighting was even throughout the room. Spatial memory is assessed by recording the latency time for the animal to escape from the water onto a submerged escape platform during the learning phase. The mice were subjected to four trials per day for 5 consecutive days. The mice were allowed to stay on the platform for 15 s before and after each trial. The time that it took for an animal to reach the platform (latency period) was recorded. Twenty-four hours after the learning phase, the mice swam freely in the water tank without the platform for 60 s, and the time spent in the region, and number of passes through the region and the quadrant of the original platform were recorded. Monitoring was performed with a video tracking system (Noldus Ltd, Ethovision XT, Holland).
Following behavioural tests, mice were randomly chosen and deeply anaesthetised with sodium pentobarbital (100 mg/kg intraperitoneally). Brains were removed and dissected through the midsagittal plane. The mice brain (n = 4) was rinsed with ice-cold isotonic saline and then homogenised with ice-cold 0.1 mmol/l phosphate buffer (pH 7.4). The homogenates (10 %w/v) were then centrifuged at 10,000 g for 15 min and the supernatant was used for biochemical estimations. One hemisphere (n = 6) was immediately coronally sectioned. The sections were fixed with 4 % paraformaldehyde for 20 min, then immersed into 0.01 M PBS for 30 min, followed by ethanol for 2 min. Sections were stored at −20 °C until immunostaining was performed. The remaining hemibrains (n = 6) were stored at −70 °C for Aβ quantitation. The mice brain (n = 4) were directly homogenised in RIPA buffer containing 0.1 % PMSF and 0.1 % protease inhibitor cocktail (Sigma, MO, USA). The lysates were centrifuged at 14,000 g for 30 min at 4 °C and the supernatant was used for protein analyses. The protein concentration in supernatants was determined using the BCA method.
To demonstrate Aβ deposition, mice were anaesthetised with a mixture of Zoletil 50 (Virbac, Carros, France) and Rompun (Bayer Korea, Seoul, Korea) solution (3 : 1 ratio, 1 ml/kg, i.p.) and perfused transcardially with a freshly prepared solution of 4 % paraformaldehyde in PBS. After the mice were decapitated, their brains were dissected from the skull. Serial 30-μm-thick coronal tissue sections were cut using a freezing microtome (Leica, Nussloch, Germany). One of every four sections was selected and mounted onto slides for immunohistochemical staining. All brain sections chosen for staining were on a similar sagittal plane and contained approximately the same area of hippocampus. Free-floating sections were incubated with the following the primary antibodies: rabbit anti-β-amyloid (1 : 1000; Cell Signaling Technology, USA) and mouse anti-NeuN (1 : 500; Millipore, Schwalbach, Germany) overnight at 4 °C. After washes in PBS, the sections were incubated with the following secondary antibodies: goat anti-rabbit Alexa 594 (1 : 500; Invitrogen) and goat anti-mouse Alexa 488 (1 : 500; Invitrogen) for 1 h. All sections were counterstained with 4′-6-diamidino-2-phenylindole before mounting and analysed on a confocal laser scanning microscope (FluoView FV 10i; Olympus, Center Valley, PA, USA). Immunofluorescence images of the cortex and hippocampus were taken using a fluorescence microscope (FluoView FV 10i; Olympus). To analyse amyloid plaque burden, the number of immunofluorescence-positive pixels in the cortex and hippocampus areas from the acquired images was analysed using the Image J processing software (National Institutes of Health, Bethesda, MD, USA).
Quantitation of Aβ in Brain Extracts
The extraction of soluble and insoluble Aβ species (including Aβ40 and Aβ42) of the cortex and hippocampus homogenates was described in previous studies (Handattu et al. 2009; Paris et al. 2010; Shankar et al. 2008). Briefly, the frozen mouse cortex and hippocampus were weighed and homogenised with ice-cold Tris-buffered saline (TBS) consisting of 20 mM Tris–HCl, 150 mM NaCl and pH 7.4 to the frozen cortex at 4: 1 (TBS volume/brain wet weight). The homogenate was centrifuged at 4 °C for 30 min at 20,000 g. The supernatant containing soluble Aβ peptide fraction (called TBS extract) was aliquoted and then stored at −80 °C, and the pellet containing insoluble Aβ was sonicated in an equal volume (v/v) of TBS plus 5 M guanidine HCl, pH 8.0, and incubated for 3–4 h at room temperature. The homogenates were centrifuged at 4 °C for 30 min at 20,000 g. The supernatant was collected (called GuHCl extract) and regarded as the insoluble Aβ peptide fraction. Protein concentrations were estimated in both fractions using the NanoDrop 2000 spectrophotometer (Thermo Scientific, Wilmington, DE, USA). Aβ40 and Aβ42 levels were quantified by ELISA according to the manufacturer’s recommendations (Invitrogen, CA, USA).
H2O2, MDA, GSH and T-AOC in brain tissue were measured. Levels of MDA were evaluated by the thiobarbituric acid reactive substances method (Ohkawa et al. 1979). Levels of H2O2 were measured using an assay kit (DE3700; R&D Systems, Minneapolis, MN, USA). Levels of GSH were measured using the GSH-400 colorimetric assay kit (Promega, Madison, WI, USA). Levels of T-AOC were measured using assay kit ab65329 (Abcam). The protein concentration in brain homogenates was determined by the Bradford method using BSA as a standard (Bradford 1976).
Western Blot Analysis
Following behavioural assessment, animals were deeply anaesthetised with isoflurane and sacrificed by decapitation. The hippocampus (n = 4 each) was directly homogenised in RIPA buffer containing 0.1 % PMSF and 0.1 % protease inhibitor cocktail (Sigma, MO, USA). The lysates were centrifuged at 14,000 g for 30 min at 4 °C and the supernatant was used for protein analyses. The protein concentration in supernatants was determined using the BCA method. Equal amounts of soluble protein were separated by SDS-PAGE and transferred onto a nitrocellulose membrane (Immobilon NC; Millipore, Molsheim, France). Immunoblotting was performed with antibodies specific for phospho-CREB(Ser133), CREB (1:1000), p-AKT (Ser473, 1:1000), AKT (1:1000), p-GSK3β (Ser9,1:1000), GSK3β (1:1000) (Cell Signalling Technology), BDNF (1:1000) (Abcam). Primary antibodies were visualised using anti-rabbit HRP-conjugated secondary antibodies (Santa Cruz Biotechnology, Inc.) and a chemiluminescent detection system (Western blotting Luminal Reagent; Santa Cruz Biotechnology, Inc.). Variations in sample loading were normalised relative to GAPDH.
All data were expressed as the mean ± SEM. For the Morris water maze tests, escape latency in the hidden platform trial were analysed with two-way ANOVA of repeated measures, while one-way ANOVA was conducted on the data obtained from the probe trial. The other data were analysed by one-way ANOVA, followed by LSD. All analyses were performed with SPSS statistical package (version 13.0 for Windows, SPSS Inc., USA). Differences were considered significant at a p value < 0.05.
Astilbin Ameliorates Recognition Memory of APPswe/PS1dE9 Mice in Novel Object Recognition
Astilbin Improves the Learning and Memory of APPswe/PS1dE9 Mice in the Morris Water Maze
In the probe test, the frequency of crossing the platform was measured for 60 s on the 6th day after the last acquisition test. As shown in Fig. 2b, there was a significant overall group difference in the frequency of crossing the platform amongst the five groups (F (4, 65) = 12.52 p < 0.01). The frequency decreased by 52.4 % in APPswe/PS1dE9 mice compared with WT mice (p < 0.01). Compared with APPswe/PS1dE9 mice, the number of platform crossings significantly increased by 1.12-fold in the Aricept-treated group (p < 0.01) and by 85.5 % in the 40 mg/kg astilbin treatment groups (p < 0.01) (Fig. 2b). In addition, there was no significant difference in swimming speed (Fig. 2c) and path length (Fig. 2d) in the probe test between the five groups of mice (p > 0.05). Furthermore, the results have shown that there was no significant gender difference in the performance of the probe test between the five groups of mice (data not shown).
Astilbin Treatment Reduces Plaque Pathology in APPswe/PS1dE9 Mice
Astilbin Decreases Aβ Levels in the Brains of APPswe/PS1dE9 Mice
Astilbin Alleviates Oxidative Stress in APPswe/PS1dE9 Mice
Astilbin Restores the Expressions of Both p-CREB and BDNF in APPswe/PS1dE9 Mice
Astilbin Increases the Activity of AKT/GSK-3β Signalling Pathway in APPswe/PS1dE9 Mice
In the present study, we found astilbin ameliorated cognitive deficits, as indicated by enhancing learning and memory (i.e. increasing recognition index by 53.9 % in the novel object recognition test and inducing a 85.5 % increase in the crossing-target number in the probe test) in this animal model of AD. The results demonstrated that astilbin reduced plaque burden and Aβ levels, up-regulated the expression of both BDNF and CREB, and increased the activity of AKT/GSK-3β signalling pathway in the hippocampus of APPswe/PS1dE9 transgenic mouse model of AD.
Since the accumulation of Aβ peptides in the brain is a central event of AD pathogenesis (Blessed et al. 1968; Cummings and Cotman 1995) and strongly associates with cognitive decline (Perry et al. 1978), we analysed neuropathological changes after astilbin treatment. In our present study, the intensity of Aβ positive staining decreased significantly following astilbin treatment observed in the cortex and hippocampus. Overall, neuropathological findings confirm that astilbin can reduce amyloid plaque burden located in the brain of the transgenic mouse. We speculated that these changes are beneficial to learning and memory.
The fact that astilbin affects the plaque burden suggests that it may influence Aβ metabolism in the brain. We observed suppressed soluble Aβ (including Aβ1-40 and Aβ1-42) levels in the hippocampus of astilbin-treated mouse. A recent study has shown that soluble Aβ is associated with AD (Mc Donald et al. 2010). Especially, the relative levels of Aβ42 are the key regulators of Aβ aggregation into amyloid plaques. Thus, Aβ42 has been implicated as the initiating molecule in the pathogenesis of AD (Golde 2007; McGowan et al. 2005). Additionally, Aβ40 associates with amyloid deposits (Gravina et al. 1995) and also causes age-dependent learning defects (Iijima et al. 2004).The decreased soluble Aβ level after astilbin treatment may explain its ameliorating effects on hippocampus-dependent tasks of learning and memory tested by NOR and MWM. Further studies are needed to investigate the possible mechanisms of astilbin on Aβ metabolism, including Aβ production and clearance. In our study, endogenous Aβ40 and Aβ42 levels were also detected in the wild-type mice brain, which coincides with previous reports (Sano et al. 2006).
Under pathological conditions of memory impairment, various signalling pathways are related with memory-enhancing pathways. These pathways eventually converge to the CREB, which plays a critical role both in long-term consolidation and indirect regulation of short-term memory. Reduced phosphorylation of CREB has been observed in post-mortem brains of AD patients. It seems that impaired CREB phosphorylation is involved in AD pathophysiology (Scott Bitner 2012). Agents that enhance the activity of CREB have been suggested to facilitate memory consolidation through increasing gene expression that is important for long-term memory (Williams and Spencer 2012). It was shown that flavonoids increased expression and release of BDNF from the synapse through enhanced CREB activation (Spencer et al. 2009; Vauzour et al. 2008). BDNF levels are reduced in AD and this has been shown to correlate with loss of cognition function (Peng et al. 2009; 2005). These signals are active in the hippocampus related to memory, learning and cognition (Cho et al. 2013). Our results indicate that astilbin can significantly increase the CREB phosphorylation and subsequent BDNF expression in the hippocampus that is observed in APPswe/PS1dE9 transgenic mice to that which is observed in WT mice (Fig. 6). The cognitive-enhancing effects of astilbin in vivo were well correlated with the up-regulation of the CREB/BDNF pathway which plays a crucial role in inducing synaptic plasticity and cognition.
BDNF, a potent neurotrophic factor, activates a variety of signalling cascades, including the PI3K/Akt, the Ras-mitogen-activated protein kinase (MAPK) and the cAMP/protein kinase A (PKA) (Brunet et al. 2001; Johnson-Farley et al. 2006). It was shown that activation of TrkB by BDNF promotes neuronal survival largely through the PI3K/Akt (Jantas et al. 2009; Yoshii and Constantine-Paton 2007). Increasing evidence suggests that the PI3K/Akt survival pathway is directly impacted by Aβ exposure and is altered in AD brains (Jimenez et al. 2011). GSK-3β, an important substrate of Akt, has been implicated in the regulation of cell survival and cognition (Brunet et al. 2001; Hooper et al. 2008). Furthermore, inhibition of GSK-3β activity can enhance the protective effects of BDNF through promoting BDNF-dependent TrkB endocytosis in neuronal and mouse model of AD (Liu et al. 2014). Based on this information, we hypothesised that the PI3K/Akt/GSK-3β signalling pathway could be involved in astilbin neuroprotective effect in our experimental model. We observed that Akt/GSK-3β signalling was suppressed in hippocampus of APPswe/PS1dE9 transgenic mice, while astibin treatments could increase the activity of Akt/GSK-3β signalling. This effect leads us to believe that astilbin may be exerting its neuroprotective effect through up-regulating BDNF which in turn activates Akt and inhibits GSK-3β. GSK-3β promotes Aβ production (McLoughlin and Miller 1996) and participates in APP processing (Ryder et al. 2003; Takashima et al. 1998). The inhibition of GSK-3β can decrease Aβ deposition in both animal models (DaRocha-Souto et al. 2012; Ryder et al. 2003; Su et al. 2004) and in cell lines (Sun et al. 2002) and attenuate Aβ-induced neurotoxicity (DaRocha-Souto et al. 2012; Takashima et al. 1993). The positive effect of astilbin on preventing the formation of senile plaques may be caused by an inhibition of GSK-3β.
In conclusion, astilbin improves learning and memory deficits in APPswe/PS1dE9 transgenic mouse model of AD and this is partly mediated by an activation of CREB/BDNF signalling pathway. These cognitive-enhancing effects of astilbin might result from inhibiting the accumulation of Aβ. Based on these findings, astilbin could be a potential therapeutic agent against AD through multiple cognitive-enhancing mechanisms.
The present work was supported by National Natural Science Foundation of China (U1304806), the China Scholarship Council (No.201408410296), the Young Backbone Teachers Assistance Scheme of Henan Province Colleges and Universities, and the Scientific Research Fund of Henan University of Science and Technology (No.09001664).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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