BackgroundSarsasapogenin (Sar) shows good effects on diabetic nephropathy (DN) through inhibition of the NLRP3 inflammasome, yet the potential mechanism is not well known.PurposeThis study was designed to explore the regulation of thrombin and/or its receptor protease-activated receptor 1 (PAR-1) on the NLRP3 inflammasome and NF-κB signaling in DN condition, and further expounded the molecular mechanism of Sar on DN.MethodsStreptozotocin-induced diabetic rats were treated by gavage with Sar (0, 20 and 60 mg/kg) for consecutive 10 weeks. Then urine and serum were collected for protein excretion, creatinine, urea nitrogen, and uric acid assay reflecting renal functions, renal tissue sections for periodic acid-Schiff staining and ki67 expression reflecting cell proliferation, and renal cortex for the NLRP3 inflammasome and NF-κB signaling as well as thrombin/PAR-1 signaling. High glucose-cultured human mesangial cells (HMCs) were used to further investigate the effects and mechanisms of Sar.ResultsSar markedly ameliorated the renal functions and mesangial cell proliferation in diabetic rats, and suppressed activation of the NLRP3 inflammasome and NF-κB in renal cortex. Moreover, Sar remarkably down-regulated PAR-1 in protein and mRNA levels but didn't affect thrombin activity in kidney, although thrombin activity was significantly decreased in the renal cortex of diabetic rats. Meanwhile, high glucose induced activation of the NLRP3 inflammasome and NF-κB, and increased PAR-1 expression while didn't change thrombin activity in HMCs; however, Sar co-treatment ameliorated all the above indices. Further studies demonstrated that PAR-1 knockdown attenuated activation of the NLRP3 inflammasome and NF-κB, and Sar addition strengthened these effects in high glucose-cultured HMCs.ConclusionSar relieved DN in rat through inhibition of the NLRP3 inflammasome and NF-κB by down-regulating PAR-1 in kidney. 相似文献
Justicidin A is a structurally defined arylnaphthalide lignan, which has been shown anti-cancer activity; however, the neuroprotective effect of justicidin A is still untested. In this study, we investigated the action of justicidin A on amyloid beta (Aβ)25–35-induced neuronal cell death via inhibition of the hyperphosphorylation of tau and induction of autophagy in SH-SY5Y cells. Pretreatment with justicidin A significantly elevated cell viability in cells treated with Aβ25–35. Western blot data demonstrated that justicidin A inhibited the Aβ25–35-induced up-regulation the levels of hyperphosphorylation of tau in SH-SY5Y cells. In addition, treatment with justicidin A significantly induced autophagy as measured by the increasing LC3 II/I ratio, an important autophagy marker. These studies showed that justicidin A inhibited activity of glycogen synthase kinase-3beta (GSK-3β), which is an important kinase in up-stream signaling pathways; inhibited hyperphosphorylation of tau in AD; and enhanced activity of AMP-activated protein kinase (AMPK), which is the key molecule for both hyperphosphorylation of tau and induction of autophagy. These data provide the first evidence that justicidin A protects SH-SY5Y cells from Aβ25–35-induced neuronal cell death through inhibition of hyperphosphorylation of tau and induction of autophagy via regulation the activity of GSK-3β and AMPK, and they also provide some insights into the relationship between tau protein hyperphosphorylation and autophagy. Thus, we conclude that justicidin A may have a potential role for neuroprotection and, therefore, may be used as a therapeutic agent for AD.
Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer’s disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R?/? mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R?/? mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R?/? mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3β activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3β disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3β pathway. These findings proved that CB2R/AMPK/GSK3β pathway can be a promising new drug target for AD. 相似文献
Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. In recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. In addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. With age, neurodegenerative changes in the brain of OXYS rats become amplified. We have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMD-like retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD. 相似文献
We previously reported that the dried peel powder of Citrus kawachiensis exerted anti-inflammatory effects in the brain in several animal models. Hyperglycemia induces inflammation and oxidative stress and causes massive damage in the brain; therefore, we herein examined the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the streptozotocin-induced hyperglycemia mice model and in the type 2 diabetic db/db mice model. The C. kawachiensis administration inhibited microglial activation in the hippocampus in the streptozotocin-injected mice. Moreover, The C. kawachiensis treatment inhibited astroglial activation in the hippocampus and the hyperphosphorylation of tau at 231 of threonine and 396 of serine in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in the db/db mice. It was suggested that the dried peel powder of C. kawachiensis exerts anti-inflammatory and neuroprotective effects in the brain. 相似文献
G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase whose dysfunction results in cognitive impairment and Alzheimer-like pathology, including tau hyperphosphorylation. However, the mechanisms whereby GRK5 influences tau phosphorylation remain incompletely understood. In the current study, we showed that GRK5 influenced the phosphorylation of tau via glycogen synthase kinase 3β (GSK3β). The activity of both tau and GSK3β in the hippocampus was increased in aged GRK5-knockout mice, which is consistent with what occurs in APP/PS1 transgenic mice. Furthermore, GRK5 regulated the activity of GSK3β and phosphorylated tau in vitro. Regardless of changes of GRK5 protein levels, tau hyperphosphorylation remained reduced after GSK3β activity was inhibited, suggesting that GRK5 may specifically influence tau hyperphosphorylation by modulating GSK3β activity. Taken together, our findings suggest that GRK5 deficiency contributes to the pathogenesis of Alzheimer's disease by influencing the hyperphosphorylation of tau through the activation of GSK3β. 相似文献
Memory impairment is usually the early and most promi-nent clinical manifestation of Alzheimer disease (AD), aprogressive neurodegenerative illness characterized bygradual deposition of neuritic plaques and neurofibrillarytangles in the brain of the patie… 相似文献
Alzheimer’s disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of β-amyloid (Aβ) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Aβ oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Aβ toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Aβ peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Aβ-induced cell death; the potential toxicity of each agent alone was also determined. The data indicated that several of the compounds decreased Aβ toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Aβ. The novobiocin analogues alone were not toxic even up to 10 μM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 μM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs. 相似文献
This study tested the hypothesis that adaptation to intermittent hypoxia (AIH) can prevent overproduction of nitric oxide (NO) in brain and neurodegeneration induced by beta-amyloid (Aβ) toxicity. Rats were injected with a Aβ protein fragment (25–35) into the nucleus basalis magnocellularis. AIH (simulated altitude of 4000 m, 14 days, 4 h daily) was produced prior to the Aβ injection. A passive, shock-avoidance, conditioned response test was used to evaluate memory function. Degenerating neurons were visualized in stained cortical sections. NO production was evaluated in brain tissue by the content of nitrite and nitrate. Expression of nNOS, iNOS, and eNOS was measured in the cortex and the hippocampus using Western blot analysis. 3-Nitrotyrosine formation, a marker of protein nitration, was quantified by slot blot analysis. Aβ injection impaired memory of rats; AIH significantly alleviated this disorder. Histological examination confirmed the protective effect of AIH. Degenerating neurons, which were numerous in the cortex of Aβ-injected, unadapted rats, were essentially absent in the brain of hypoxia-adapted rats. Injections of Aβ resulted in significant increases in NOx and in expression of all NOS isoforms in brain; AIH blunted these increases. NO overproduction was associated with increased amounts of 3-nitrotyrosine in the cortex and hippocampus. AIH alone did not significantly influence tissue 3-nitrotyrosine, but significantly restricted its increase after the Aβ injection. Therefore, AIH affords significant protection against experimental Alzheimer’s disease, and this protection correlates with restricted NO overproduction. 相似文献
Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease‐initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA‐125b (miR‐125b), which is elevated in AD. In primary neurons, overexpression of miR‐125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42‐MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti‐apoptotic factor Bcl‐W are downregulated as direct targets of miR‐125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl‐W prevents miR‐125b‐induced tau phosphorylation, suggesting that they mediate the effects of miR‐125b on tau. Conversely, suppression of miR‐125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR‐125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl‐W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR‐125b in the pathogenesis of AD by promoting pathological tau phosphorylation. 相似文献
Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase‐3β at Ser 9 in the ipsilateral hippocampus. These MCAO‐induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N‐methyl‐d ‐aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B‐containing NMDARs through entorhinal–hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase‐3β is an important protein kinase involved in NMDARs‐mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B‐containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post‐stroke dementia.
Protein kinase A (PKA) plays a crucial role in tau hyperphosphorylation, an early event of Alzheimer disease (AD), and 17β-estradiol
replacement in aging women forestalls the onset of AD. However, the role of estradiol in PKA-induced tau hyperphosphorylation
is not known. Here, we investigated the effect of 17β-estradiol on cAMP/PKA activity and the PKA-induced tau hyperphosphorylation
in HEK293 cells stably expressing tau441. We found that 17β-estradiol effectively attenuated forskolin-induced overactivation
of PKA and elevation of cAMP, and thus prevented tau from hyperphosphorylation. These data provide the first evidence that
17β-estradiol can inhibit PKA overactivation and the PKA-induced tau hyperphosphorylation, implying a preventive role of 17β-estradiol
in AD-like tau pathology.
Xin-An Liu and Ling-Qiang Zhu contributed equally to this work. 相似文献
The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPARβ/δ?/? mice.Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex. 相似文献
In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology. 相似文献
We have reported that activation of glycogen synthase kinase-3 (GSK-3) by ventricle injection of wortmannin (WT) and GF-109203X (GFX) induces Alzheimer-like memory deficit in rats [Liu et al., J. Neurochem. 87 (2003), 1333]. To further explore the factors responsible for the memory loss, we studied here the temporal alterations of GSK-3, tau phosphorylation, beta-amyloid (Abeta), and acetylcholine (ACh) after injection of WT/GFX, and analyzed their correlation with the memory loss. We observed that the severe memory deficit occurred at 24 and 48 h, and simultaneously, GSK-3 activation, tau hyperphosphorylation at Thr231, Ser396, and Ser404 and decline of ACh in hippocampus were detected, and these changes were mostly recovered at 72 and 96 h after the injection of WT/GFX. Remarkable increase of Abeta and intracellular accumulation of argentophilic substances were detected at 72 h. Pearson analysis showed that the memory deficit was correlated with GSK-3 activation, tau hyperphosphorylation, and decline of ACh but not with Abeta overproduction. Our data provide direct evidence demonstrating that activation of GSK-3 by WT/GFX may cause memory deficit through tau hyperphosphorylation and suppression of ACh in hippocampus. 相似文献
AimsThe progressive accumulation of beta-amyloid peptide (Aβ), in the form of senile plaques, has been recognized as one of the major causes of Alzheimer's disease (AD) pathology. Increased production of Aβ and the aggregation of Aβ to oligomers have been reported to trigger neurotoxicity, oxidative damage and inflammation. Furthermore, Aβ-induced tau hyperphosphorylation and neurotoxicity are downstream of Aβ. Therefore, we studied the possible neuroprotective effects of caffeic acid against Aβ-induced toxicity.Main methodsTreatment of PC12 cells with 10 μM Aβ (25–35) for 24 h significantly decreased the cell viability; this was accompanied by an increase in intracellular calcium levels and tau phosphorylation with GSK-3β (glycogen synthase kinase-3β) activation (phosphorylation).Key findingsHowever, pretreatment of the PC12 cells with 10 and 20 μg/ml of caffeic acid, for 1 h prior to Aβ, significantly reversed the Aβ-induced neurotoxicity by attenuating the elevation of intracellular calcium levels and tau phosphorylation.SignificanceTaken together, these results suggest that caffeic acid protected the PC12 cells against Aβ-induced toxicity. In addition, the neuroprotective mechanisms of caffeic acid against Aβ attenuated intracellular calcium influx and decreased tau phosphorylation by the reduction of GSK-3β activation. 相似文献
Neurofibrillary tangles, one of the characteristic pathological features of Alzheimer's disease (AD), are composed of paired helical filaments mainly with hyperphosphorylated tau protein. Inhibition of the hyperphosphorylation of tau protein is an effective therapy for AD. The current study was designed to investigate the protective effects of alkaloids enriched extract from Dendrobium Nobile Lindl. (EDNLA), a Chinese medicinal herb, on hyperphosphorylation of tau protein in AD brain. Rats were administrated intragastrically with different doses of DNLA (20, 40 mg/kg) every 8 h for one day, followed by lipopolysaccharide (LPS, 100 μg) injecting into the bilateral ventricle. Two hours later, the hippocampi of each group were collected to examine the hyperphosphorylated tau protein by western blotting. Additional rats were treated by EDNLA thrice daily for one week, to examine the effects on LPS-induced apoptosis in the brain. LPS injection significantly increased the expression of hyperphosphorylated tau protein at Ser396, Ser199-202, Ser404, Thr231, Thr205 sites and GSK-3β increased, LPS also induced apoptosis in the brain. EDNLA dramatically ameliorated these abnormal changes (P < 0.05). The present study demonstrated that EDNLA attenuates LPS-induced hyperphosphorylation of tau protein in rat's hippocampus and protects against LPS-induced apoptosis in rat brain. 相似文献
Intracellular accumulating of the hyperphosphorylated tau plays a pivotal role in neurodegeneration of Alzheimer disease (AD), but the mechanisms underlying the gradually aggravated tau hyperphosphorylation remain elusive. Here, we show that increasing intracellular tau could upregulate mRNA and protein levels of TRPC1 (transient receptor potential channel 1) with an activated store‐operated calcium entry (SOCE), an increased intraneuronal steady‐state [Ca2+]i, an enhanced endoplasmic reticulum (ER) stress, an imbalanced protein kinases and phosphatase, and an aggravated tauopathy. Furthermore, overexpressing TRPC1 induced ER stress, kinases‐phosphatase imbalance, tau hyperphosphorylation and cognitive deficits in cultured neurons and mice, while pharmacological inhibiting or knockout TRPC1 attenuated the hTau‐induced deregulations in SOCE, ER homeostasis, kinases‐phosphatase balance, and tau phosphorylation level with improved synaptic and cognitive functions. Finally, an increased CCAAT‐enhancer‐binding protein (C/EBPβ) activity was observed in hTau‐overexpressing cells and the hippocampus of the AD patients, while downregulating C/EBPβ by siRNA abolished the hTau‐induced TRPC1 upregulation. These data reveal that increasing intracellular tau can upregulate C/EBPβ‐TRPC1‐SOCE signaling and thus disrupt phosphorylating system, which together aggravates tau pathologies leading to a chronic neurodegeneration. 相似文献