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Introduction
One of the neuropathological hallmarks of Alzheimer's disease (AD) is an accumulation of plaques consisting
predominately of amyloid-beta ( Aβ) peptide, which is a cleavage product of amyloid precursor protein (APP) resulting from the action
of b- and g-secretase[1]. Accompanying the accumulation of
Aβ is elevation in the inflammation-related proteins of the
complement cascade, as well as interleukin (IL)-1β and tumor necrosis
factors-a[2]. Any or all of the above mentioned
proteins are potential triggers for the neuronal death and synaptic loss. Numerous studies
have shown that Aβ-induced neuronal death demonstrates signs of
apoptosis[3,4]. However, the signal transduction
mechanism(s) by which these losses occur remains largely unknown.
The mammalian mitogen-activated protein kinases (MAPK) can be subdivided into the extracellular signal-regulated
kinases (ERKs), the Jun N-terminal kinases (JNKs), and the p38 MAPK. JNK and p38 MAPK are also called stress activated
protein kinases (SAPK). These pathways appear to be activated by a wide variety of cellular stresses including heat shock,
lipopolysaccharides (LPS), and inflammatory cytokinases. It has also been demonstrated that the p38 MAPK pathway is
hyperactive in the AD brain[5]. Activation of p38 MAPK is mediated by the upstream MAPK kinase, referred to as
mitogen-activated protein kinase kinase (MKK)3 and
MKK6[6,7]. In addition, there is the potential for crosstalk between JNK and p38
MAPK pathways because of MKK4 (SEK1), which has been shown to activate both p38 MAPK and
JNK[6]. Activated p38 MAPK phosphorylates MAPK activating protein kinase 2 (MAPKAPK-2), which phosphorylates the 27 kDa heat shock
protein (Hsp27)[8] and activating transcription factors 2
(ATF-2)[9]. Hsp27 is a molecular chaperone with an ability to interact
with a large number of proteins. Recent evidence has shown that Hsp27 regulates apoptosis through an ability to interact
with key components of the apoptotic signaling pathway, in particular, those involved in caspase activation and
apoptosis[10].
Sodium ferulate (SF), extracted from a traditional Chinese herbal medicine, has potent
antioxidant[11] and anti-inflammatory
activities[12]. It has recently been reported that long-term administration of ferulic acid protected mice against learning
and memory deficits induced by centrally administered
β-amyloid[13]. The primary site of action of ferulic acid could be the
microglia[14] and
astrocytes[15]. A recent report showed that ferulic acid inhibited the formation of
Aβ fibrils and destabilized preformed fibrillary
Aβ[16]. Sultana et al reported that ferulic acid ethyl ester significantly inhibited
Aβ1-42-induced cytoxicity, intracellular reactive oxygen species accumulation, lipid peroxidation, and the induction of inducible nitric oxide synthase in
primary hippocampal cultures[17]. In addition, ferulic acid attenuates iron-induced oxidative damage and apoptosis in
cultured neurons[18] and reduces the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase activity following
exposure to LPS[19]. Our previous report showed that SF had inhibitory effects on
induced p38 MAPK phosphorylation and neuronal apoptotic deaths in the rat
hippocampus[20]. Therefore, in this study, we investigated the effect of SF on
Aβ1-40-induced phosphorylation levels of the MKK/MKK6 and p38 MAPK as well as MAPKAPK2 and Hsp27 in rat hippocampus.
We have also studied the effect of the selective p38 MAPK inhibitor SB203580 on these kinase phosphorylations and the
pro-apoptotic pathways.
Materials and methods
Materials
Aβ1-40 (Product number, A2326; Sigma Chemical, St Louis, MO, USA) was resuspended at a concentration of
1 mmol/L in saline solution. To obtain the aggregated form of
Aβ1-40, the peptide solution was placed in an incubator at 37
°C for 48 h. SF, a colorless powder with purity >99%, was obtained from Suzhou Changtong Chemical (Suzhou, China).
SB203580 was obtained from Promega Corporation. The enhanced chemiluminescence kit was from Pierce Biotechnology
(Rockford, IL, USA). Phospho-p38 MAPK (Thr180/tyr182, #9211), phospho-MKK3/MKK6 (Ser189/207, #9231),
phospho-MAPKAPK-2 (Thr334, #3404), phospho-Hsp27(Ser82, #2401), caspase-3 (#9662), caspase-9
(Human Specific, #9502), caspase-7 (#9492), PARP (#9542), cleaved PARP (ASP330, #9541), and anti-rabbit IgG, HRP-linked antibodies and biotinylated protein
ladder detection pack (#7727) were purchased from Cell Signaling (Beverly, MA, USA).
IL-1β antibody was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA).
b-actin antibody was from Sigma Chemical. SeeBlue Plus2 Pre-stained
Standard (Catalog No LC5925) was from Invitrogen Life Technologies (USA).
Animals and drug treatment
Sprague-Dawley rats, weighing 200 g to 220 g, were used in these studies (Grade II,
Certificate No: 2003_0009, Experimental Animal Center of China Medical University). The animals were maintained at an
ambient temperature of 22_24 °C under a 12 h:12 h light:dark cycle. The rats were randomly divided into six groups:
Aβ1-40 group, Aβ1-40+SF group (100 mg/kg and 200 mg/kg), control group for
Aβ1-40 and SF (saline solution), SB203580 group
(SB203580 was dissolved in 1% dimethylsulfoxide, DMSO),
Aβ1-40+SB203580 group, and the control group for SB203580 (1%
DMSO).
The rats were anesthetized with chloral hydrate (300
mg/kg) and placed in a stereotaxic apparatus. Drugs or
vehicles were intracerebroventricularly injected into the
animals with a Hamilton microsyringe. The injection lasted 5 min and the needle with the syringe was left in place for 2 min
after the injection for the completion of the drug infusion.
In the Aβ1-40 group, the rats were injected with 5 µL
Aβ1-40. In the Aβ1-40+SF group, the rats were administered with SF ig (100 mg/kg and 200 mg/kg, daily) for 3 weeks prior to
Aβ1-40 injection. The rats in the control group for
Aβ1-40 and SF were injected with 5 µL saline solution. In the SB203580 group, the
rats were injected with 5 µL SB203580 (8 µg/rat). In the
Aβ1-40+SB203580 group, the rats were
injected with SB203580 and then with
Aβ1-40, 1 h after SB203580 injection. The rats in the SB203580 control group were
injected with 5 µL 1% DMSO.
The rats were killed by decapitation 6 h after injection with the drugs or vehicles. Hippocampal slices (500-µm thick) were
prepared and immediately frozen on dry ice. The CA1 region was microdissected using a method described in a previous
study[21] for Western blot. Seven days after injection, Nissl staining was used to observe the morphological change in the
hippocampal CA1 regions. Animals (5 in each group) used for Nissl staining were anesthetized and perfused transcardially
with 4% paraformaldelyde.
Western blot analysis Western blot was performed for the analysis of
IL-1β, MKK3/MKK6, p38 MAPK, MAPKAPK-2, Hsp27, caspase-9, caspase-7, PARP, and caspase-3. The fresh hippocampal CA1 region was homogenized in RIPA buffer [1%
Triton, 0.1% SDS, 0.5% deoxycholate, 1 mmol/L EDTA, 20 mmol/L Tris (pH 7.4), 150 mmol/L NaCl, 10 mmol/L NaF, 0.1
mmol/L PMSF]. The nuclear fractions were first isolated by centrifuging the homogenates at
7500×g at 4 °C for 30 min. The supernatant was further centrifuged at 12
000×g at 4 °C for 20 min to remove insoluble materials. Protein concentrations were
quantified by the method of Lowry. Tissue samples were equalized for protein concentration. Proteins were resolved by
10%_12% SDS-PAGE, transferred onto nitrocellulose membranes. Gels were also loaded with colored molecular weight
markers to assess electrophoretic transfer, and biotinylated protein ladder marker to estimate molecular weights of bands of
interest. The membranes were blocked with 3% BSA in TBS (pH 7.6) for 1 h and incubated overnight at 4 °C with suitably
diluted primary antibodies. After extensive washing with TTBS, the membranes were incubated with anti-rabbit IgG,
HRP-linked antibody plus anti-biotin antibody for 1 h at room temperature. The blots were detected using the enhanced
chemiluminescence (ECL) reaction. After visualization by ECL, all of the nitrocellulose strips were reprobed with
b-actin antibody to ensure equal loading of protein on all SDS-PAGE gels. Immunoreactive blots were incubated with alkaline
phosphatase-conjugated anti-mouse IgG antibody for 1 h. Finally, the blots were developed with the alkaline phosphatase substrate
O-dianisidine tetrazotized along with β-naphthyl acid phosphate. Quantification of protein bands was achieved by
densitometric analysis using Chem image 5500 software (UVP, USA).
Nissl staining Seven days after injection of
Aβ1-40, the rats (five rats of each group) were perfused transcardially with 4%
paraformaldehyde in PBS. The brains were post-fixed for 24 h and were embedded in paraffin. Serial coronal sections (5-µm
thickness) were taken from various sections of the brain, stained for Nissl body using cresyl violet, and examined for
pathological changes.
To assess hippocampal injury, the number of neurons in the pyramidal layer of the medial CA1 region was counted under
a light microscope at 400 magnification according to the method described by Zhang
et al[22]. Two continuous fields in
hippocampal CA1 subregion were selected for each section and the neurons were counted. The mean of two fields was taken
as the neuron number of this section and the mean of four sections was taken as the neuron number of this specimen.
Statistical analysis All data were presented as mean±SD. Statistical analysis was carried out with one-way ANOVA,
followed by LSD's post hoc test, which was provided by SPSS 11.5 statistical software. The level of significance was
accepted as P<0.05.
Results
Sodium ferulate inhibited the
amyloid-b1-40-induced increase in phospho-MKK3/MKK6 and phospho-p38 MAPK
expression As shown in Figure 1A, basal levels of hippocampal phospho-MKK3/MKK6 were very low. Intracere-broventricular
injection of preaggregated Aβ1-40 led to a significant increase in phospho-MKK3/MKK6 protein expres-sion. The
densitometric analysis revealed that phospho-MKK3/MKK6 level was significantly increased (5.07±0.63-fold relative to control
value). SF (100 mg/kg and 200 mg/kg) significantly inhibited
Aβ1-40-induced increase in phospho-MKK3/MKK6 expression.
However, the selective inhibitor of p38 MAPK, SB203580 (8 µg/rat) did not prevent the increase in phosphorylated
MKK3/MKK6 induced by Aβ1-40 (Figure 1A). Surprisingly, phosphorylation of the
substrate(s) of activated MKK3/MKK6, p38 MAPK, was increased by
Aβ1-40 to a smaller extent. The phospho-p38 MAPK level was modestly elevated
(1.51±0.155-fold relative to control value). The
Aβ1-40-induced increase in activation of p38 MAPK was completely prevented by SF (100 mg/kg and 200
mg/kg). SB203580 did not prevent an
Aβ1-40-induced increase in phospho-p38 MAPK expression (Figure 1B).
Effects of sodium ferulate on
amyloid-b1-40-induced phosphorylated
MAPKAPK -2 and phosphorylated Hsp27
sions It is well established that MAPKAPK-2 is phosphorylated and activated by p38 MAPK, and therefore, the effect
of Aβ1-40 on its phosphorylation state was investigated in the rat hippocampus. As shown in Figure2A, phosphorylated
MAPKAPK-2 in hippocampal CA1 prepared from
Aβ1-40-treated rats was significantly reduced compared to that in control rats. This
induced decrease in phosphorylated MAPKAPK-2 was partly reversed by SF (100 mg/kg and 200 mg/kg). SB203580 (8 µg/rat), the p38 MAPK selective inhibitor,
completely inhibited the MAPKAPK-2 phos-
expresphorylation.
The phosphorylation state of Hsp27 was assessed by immunoblot using a rabbit polyclonal antibody that detects the
phosphorylated Hsp27 at Ser82. The results showed that intracerebroventricular injection of
Aβ1-40 led to the
decrease in Hsp27 phosphorylation, being consistent with the change of MAPKAPK-2 phosphorylation induced by
Aβ1-40. SF (100 mg/kg and 200 mg/kg) partly reversed the effect of
Aβ1-40 on phosphorylated Hsp27. In addition, SB203580
significantly inhibited Hsp27 phosphorylation (Figure 2B). All the above results support the conclusion that in rat hippocampus
the phosphorylation of Hsp27 is catalysed by MAPKAPK-2, which is one of the p38 MAPK substrates. However, in
SB203580 control group, 1% DMSO did not show significant effects on phosphorylated MAPKAPK-2 and Hsp 27
expressions compared with the saline solution group (data not shown).
Sodium ferulate and SB203580 inhibit the amyloid-
b1-40-induced increase in IL-1β protein level
The sample immunoblot and mean data in Figure 4 indicated that the expression
of IL-1β in hippocampal samples prepared from Aβ-treated rats was significantly increased compared to samples from control
rats. SF (100 mg/kg and 200 mg/kg) markedly inhibited an
induced increase in IL-1β expression. SB303580 completely
abolished an Aβ-induced increase in IL-1β expression, suggesting that
induced increase in IL-1β expression in the hippocampus is mediated through p38 MAPK pathway (Figure 3).
Sodium ferulate attenuates the
amyloid-b1-40-induced caspase cascades and PARP cleavage
To test the influence of SF on
Aβ1-40-induced neurotoxicity, the expressions of procaspase-9, procaspase-3, procaspase-7, and their cleavage products
were analyzed by immunoblotting. The results showed that intracerebroventricular injection of preag-gregated
Aβ1-40 led to the processing of inactive procaspase-9 into their active forms. Procaspase-9 proteolysis was confirmed by the increase of
a 37 kDa fragment in hippocampal CA1. SF (100 mg/kg and 200 mg/kg) significantly prevented
Aβ1-40-induced procaspase-9 cleavage. However, SB203580 did not inhibit
Aβ1-40-induced pro-caspase-9 cleavage (Figure 4A). According to the picture
of the apoptotic pathway, caspase-9 activity is responsible for procaspase-3 and procaspase-7 activation
(executioner caspases) by proteolytic cleavage.
Procaspase-3 and procaspase-7 processing was investigated by Western blotting.
Aβ1-40 induced procaspase-3 processing and caspase-3 activation, as demonstrated in Figure 4B by the appearance of p19 fragments.
Similarly, caspase-7 was also cleaved to its p19 active form (Figure 4C) in
treated rat hippocampus. Both SF (100 mg/kg and 200 mg/kg) and SB203580 inhibited caspase-3 and caspase-7 activation induced by
Aβ1-40. Altogether, these observations indicated that SF interfered with the activation of three procaspases: procaspase-9, -3, and -7.
During apoptosis, PARP is one of the earliest targets for caspase-3 cleavage which results in the formation of an 89 kDa
C-terminal fragment containing the catalytic domain and a 24 kDa fragment that binds DNA
ends[23]. As shown in Figure 4D, its expression level was significantly lower in hippocampal CA1 region prepared from
treated animals and was associated with the appearance of the 89 kDa fragment of PARP. In SF-treated animals, the expression level of intact PARP (116 kDa) was
higher while the expression of the 89 kDa fragment was lower when compared with that of
treated animals. SB203580 significantly prevented
induced PARP cleavage (Figure 4D).
Effect of sodium ferulate on the
amyloid-b1-40-induced morphological change and number of hippocampal CA1
pyramidal neurons The arrangement of hippocampal CA1 pyramidal neurons of the control group was clearly discernible (Figure
5A). The arrangement of hippocampal pyramidal neurons of
Aβ1-40-treated group was sparse and the Nissl body was
decreasing or dissolving (Figure 5B). The arrangements of pyramidal neurons of
Ab+SF (100 and 200 mg/kg) groups were better than that of the
Aβ1-40-treated group (Figure 5C, 5D). The number of hippocampal CA1 pyramidal neurons of the
Aβ1-40-treated group (32±6,
n=5) was significantly less than that of the control group (69±3,
n=5) and SF 100 mg/kg (66±5, n=5) and
200 mg/kg (72±10, n=5). No significant difference was detected between the control group and SF groups.
Discussion
We report here that
Aβ1-40 induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in
hippocampal tissue. This increase, in combination with
enhanced IL-1β protein expression, mediated the Aβ-induced activation of the pro-apoptotic pathways, the caspases. SF
significantly prevented an Aβ-induced increase in MKK3/MKK6, p38 MAPK and
IL-1β. Similarly, SF remarkably inhibited Aβ-induced activation of procaspase 9 and the subsequent procaspase 3 and procaspase 7, and cleavage of PARP. In
addition, one of the most interesting aspects of the present results was the discrepancy between the changes
in p38 MAPK and the corresponding
phospho-MAPKAPK-2. It is obvious from Figure 1B and Figure 2 that intracerebroven-tricular
injection of Aβ1-40 elevated phospho-p38 MAPK
expression, but reduced its substrates,
phospho-MAPKAPK-2 and phospho-Hsp27 protein expression. SF reversed
Aβ1-40 induced these changes. In other words, SF significantly prevented
Aβ1-40-induced decrease in
phospho-MAPKAPK-2 and phospho-Hsp27. Our evidence indicates that SF may exert its neuroprotective effect by decreasing activation of
caspase-9,-3, and -7 and PARP cleavage.
Activation of p38 MAPK is involved in neuronal
response to various stresses[24], and this kinase is closely related to hyperphosphorylated tau protein in
AD[25]. Our result and previous studies demonstrated that
induced increase in p38 MAPK activation was accompanied by the increase in
IL-1β[26]. SB203580, a selective p38 MAPK
inhibitor, completely abolished Aβ-induced increase in
IL-1β protein expression, indicating that Aβ-induced increase in
IL-1β was mediated through p38 MAPK pathway. Over-expression of
IL-1β observed in the AD brain contributes to the neuronal dysfunction and loss characteristic of AD, particularly those involved in
formation of neurofibrillary tangle and loss of synapse. In addition,
IL-1β upregul-ates expression and stimulates the processing of the
Ab precursor protein, resulting in amyloidogenic fragments in
neurons[27]. In this way, IL-1β may sustain
and enhance plaque formation. Alternatively, Aβ, phospho-tau or
IL-1β may be the stressors of p38 MAPK/JNK. Positive
feedback loops may be present in the AD brain whereby the initial stressor is amplified via MAPK pathway activation. SF can
inhibit p38 MAPK and IL-1β production, thereby blocking this vicious cycle.
Downstream of p38 MAPKs, there is diversification and extensive branching of signaling pathways. One of the p38
MAPK substrates is MAPKAPK-2, which phosphorylates
Hsp27[8]. Our results also demonstrated that SB203580
completely prevented phospho-MAPKAPK-2 protein expres-sion, but partly inhibited phospho-Hsp27 expression,
suggesting that in rat hippocampus the upstream of
MAPKAPK-2 is p38 MAPK, while the downstream is Hsp27.
In this study, we investigated the effect of
Aβ1-40 on phosphorylated MAPKAPK-2 and Hsp27 and effect of SF. Surprisingly,
our results showed that intracerebroventricular injection of
Aβ1-40 reduced phosphorylated MAPKAPK-2 and
Hsp27 protein expressions. SF significantly prevented
Aβ1-40-induced decrease in phosphorylated MAPKAPK-2 and
Hsp27 protein expression. This might be the other mechanism by which SF-inhibited
Aβ1-40 induced the activation of the pro-apoptotic
pathways, caspases, of hippocampal
neurons. In recent years, evidence has accumulated to show that Hsp27 has cellular
protection of the central nervous system. Hsp27 acts via two mechanisms to confer cellular protection. First, as molecular
chaperones, Hsp27 are active in the formation and maintenance of the native conformation of cytosolic
protein[28] and stabilization of the actin filaments, which make up the cytoskeleton of the
cell[29]. Second, Hsp27 functions in neuroprotection
through anti-apoptotic actions, particularly on the mitochondrial pathway of caspase-
dependent cell death. One of the main mechanisms of
caspase activation involves the release of cytochrome c from
mito-chondria. Cytochrome c interacts and binds with the Apaf-1 resulting in an apoptosome. The apoptosome recruits and
activates procaspase-9, which recruits, cleaves and activates caspase-3 and caspase-7. It is these two caspases that
mediate the death of the cell through selective
proteolysis[30]. Hsp27 inhibits apoptosis by modulating a component of this pathway.
Hsp27 inhibits the release of cytochrome
c[31] and the formation of a functionally competent apoptosome. Hsp27 binds with
cytochrome c after its release from the mitochondria to prevent its interaction with
Apaf-1[32]. Hsp27 acts to prevent the activation of caspase-3 directly or via a mechanism similar to Bcl-2, which delays PARP cleavage and procaspase-3
activation[33,34]. Therefore, this has led to the hypothesis that Hsp27 may be useful in the treatment of neurodegenerative diseases.
In summary, our finding indicates that SF reduces caspase-9, -3, and -7 expression and activity and PARP cleavage. This
inhibitory effect of SF on the activation of the pro-apoptotic pathways, the caspases, might occur through reduction of
inflammatory cytokine IL-1β production and p38 MAPK activity and an increase of Hsp27
expression in rat hippocampus.
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