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1.
Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels
is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death
and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone
(CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several
pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work
shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study,
we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron
microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells.
MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced
Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS
may be useful in the inhibition or prevention of AD development and progression. 相似文献
2.
3.
Anna Colell Anna Fernández José C. Fernández-Checa 《Journal of bioenergetics and biomembranes》2009,41(5):417-423
The molecular mechanisms of Alzheimer’s disease (AD) are not fully understood. Extensive evidence from experimental models
has involved the overgeneration and accumulation of toxic amyloid β peptides (Aβ) in the onset and progression of the disease.
The amyloidogenic processing of amyloid precursor protein into pathogenic Aβ fragments is thought to occur in specific domains
of the plasma membrane and favored by cholesterol enrichment. Intracellular Aβ accumulation is known to induce oxidative stress,
predominantly via mitochondria targeting of toxic Aβ. Recent evidence using mouse models of cholesterol loading has demonstrated
that the specific mitochondrial cholesterol pool sensitizes neurons to Aβ-induced oxidant cell death and caspase-independent
apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial
membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against Aβ-mediated
neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in
addition to fostering Aβ generation, mitochondrial cholesterol determines Aβ neurotoxicity via mGSH regulation. 相似文献
4.
Alzheimer’s disease is a progressive neurodegenerative disorder that affects primarily learning and memory functions. There
is significant neuronal loss and impairment of metabolic functioning in the temporal lobe, an area believed to be crucial
for learning and memory tasks. Aggregated deposits of amyloid β-peptide may have a causative role in the development and progression
of AD. We review the cellular actions of Aβ and how they can contribute to the cytotoxicity observed in AD. Aβ causes plasma
membrane lipid peroxidation, impairment of ionmotive ATPases, glutamate uptake, uncoupling of a G-protein linked receptor,
and generation of reactive oxygen species. These effects contribute to the loss of intracellular calcium homeostasis reported
in cultured neurons. Many cell types other than neurons show alterations in the Alzheimer’s brain. The effects of Aβ on these
cell types is also reviewed. 相似文献
5.
Alzheimer’s disease (AD) is characterized by the depositions of amyloid-β (Aβ) proteins, resulting in a reduction of choline
acetyltransferase (ChAT) activity of AD brain in the early stages of the disease. Several growth factors, including brain-derived
neurotrophic factor (BDNF), insulin-like growth factor (IGF)-1 and glial cell-derived neurotrophic factor (GDNF) are known
to protect neuronal cell death in several neurodegenerative both in vitro and in vivo models. In this study, septal neurons
were prepared from septal nucleus of embryonic (day 16-17) rat brain and treated with monomeric, oligomeric or fibrillar Aβ1-42 peptide. Oligomeric Aβ1-42, (10 μM) was the most potent at sublethal dose. Septal neuron cultures treated with BDNF, IGF-1 or GDNF or co-cultured with
genetically modified human neural progenitor cells (hNPCs) secreting these neurotrophic factors (but not allowing contact
between the two cell types), were protected from oligomeric Aβ1-42 peptide-induced cell death, and these trophic factors enhanced cholinergic functions by increasing ChAT expression level.
These results indicate the potential of employing transplanted hNPCs for treatment of AD. 相似文献
6.
Amyloid-beta peptide (Aβ) is known to induce the redox imbalance, mitochondrial dysfunction and caspase activation, resulting
in neuronal cell death. Treatment with antioxidants provided a new therapeutic strategy for Alzheimer’s disease (AD) patients.
Here we investigate the effects of purple sweet potato anthocyanins (PSPA), the known strong free radical scavengers, on Aβ
toxicity in PC12 cells. The results showed that pretreatment of PC12 cells with PSPA reduced Aβ-induced toxicity, intracellular
reactive oxygen species (ROS) generation and lipid peroxidation dose-dependently. In parallel, cell apoptosis triggered by
Aβ characterized with the DNA fragmentation and caspase-3 activity were also inhibited by PSPA. The concentration of intracellular
Ca2+ and membrane potential loss associated with cell apoptosis were attenuated by PSPA. These results suggested that PSPA could
protect the PC-12 cell from Aβ-induced injury through the inhibition of oxidative damage, intracellular calcium influx, mitochondria
dysfunction and ultimately inhibition of cell apoptosis. The present study indicates that PSPA may be a promising approach
for the treatment of AD and other oxidative-stress-related neurodegenerative diseases. 相似文献
7.
Amyloid beta-protein (Aβ) is the major component of senile plaques and cerebrovascular amyloid deposits in individuals with
Alzheimer’s disease. Aβ is known to increase free radical production in neuronal cells, leading to oxidative stress and cell
death. Recently, considerable attention has been focused on dietary antioxidants that are able to scavenge reactive oxygen
species (ROS), thereby offering protection against oxidative stress. Walnuts are rich in components that have anti-oxidant
and anti-inflammatory properties. The inhibition of in vitro fibrillization of synthetic Aβ, and solubilization of preformed
fibrillar Aβ by walnut extract was previously reported. The present study was designed to investigate whether walnut extract
can protect against Aβ-induced oxidative damage and cytotoxicity. The effect of walnut extract on Aβ-induced cellular damage,
ROS generation and apoptosis in PC12 pheochromocytoma cells was studied. Walnut extract reduced Aβ-mediated cell death assessed
by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, and release of lactate dehydrogenase (membrane
damage), DNA damage (apoptosis) and generation of ROS in a concentration-dependent manner. These results suggest that walnut
extract can counteract Aβ-induced oxidative stress and associated cell death. 相似文献
8.
Buntup D Skare O Solbu TT Chaudhry FA Storm-Mathisen J Thangnipon W 《Neurochemical research》2008,33(2):248-256
β-Amyloid (Aβ) peptides may cause malfunction and death of neurons in Alzheimer’s disease. We investigated the effect of Aβ
on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated
with Aβ(25-35) at 3 and 10 μM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed
neuronal–glial cell cultures (from P1 rats), Aβ reduced the concentration of system A glutamine transporter 1 (SAT1), by up
to 50% expressed relative to the neuronal marker microtubule-associated protein 2 (MAP2) in the same cell. No significant
effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter
1 (SN1). In neuronal cell cultures (from E18 rats), Aβ(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed
effect depends on the presence of astroglia. The results indicate that Aβ may impair neuronal function and transmitter synthesis,
and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake.
Special issue article in honor of Dr. Frode Fonnum. 相似文献
9.
Jhamandas JH Mactavish D 《Apoptosis : an international journal on programmed cell death》2012,17(1):37-47
Deposition of amyloid-beta (Aβ) protein, a 39–43 amino acid peptide, in the brain is a major pathological feature of Alzheimer’s
disease (AD). We have previously provided evidence that in primary cultures of rat basal forebrain and human fetal neurons
(HFNs), neurotoxic effects of oligomeric Aβ are expressed through the amylin receptor. In this study, we utilized RT-PCR arrays
to compare RNA expression levels of 84 markers for pro and anti- apoptotic signalling pathways following exposure of HFNs
to either Aβ1-42 (20 μM) or human amylin (2 μM). Oligomeric Aβ1-42 or human amylin was applied to HFNs alone or after pre-treatment of cultures with the amylin receptor antagonist, AC253.
Changes in RNA levels were then quantified and compared to each other in order to identify increases or decreases in gene
expression of apoptotic markers. Applications of Aβ1-42 or human amylin, but not the inactive inverse sequence Aβ42-1 or rat amylin, resulted in a time-dependent marked increase in mediators of apoptosis including a 10- to 30-fold elevations
in caspases 3, 6, 9, BID and XIAP levels. Amylin receptor antagonists, AC253 (10 μM) or AC187 (10 μM), significantly attenuated
the induction of several pro-apoptotic mediators up-regulated following exposure to Aβ1-42 or human amylin and increased the expression of several anti-apoptotic markers. These data allow us to identify key elements
in the Aβ-induced apoptosis that are blocked by antagonism of the amylin receptor and further support the potential for amylin
receptor blockade as a potential therapeutic avenue in AD. 相似文献
10.
The neurotoxicity of the amyloid-β peptide (Aβ) appears to be, at least in part, related to pathological activation of glutamate
receptors by Aβ aggregates. However, the downstream signaling pathways leading to neurodegeneration are still incompletely
understood. Hyperactivation of nitric oxide synthase (NOS) and increased nitric oxide (NO) production have been implicated
in excitotoxic neuronal damage caused by overactivation of glutamate receptors, and it has been suggested that increased NO
levels might also play a role in neurotoxicity in Alzheimer’s disease. We have examined the effect of blockade of NO production
on the neurotoxicity instigated by Aβ42 and by elevated concentrations of glutamate in chick embryo retinal neurons in culture. Results showed that l-nitroarginine methyl ester, a potent inhibitor of all NOS isoforms, had no protective effect against neuronal death induced
by either Aβ42 (20 μM) or glutamate (1 mM). Surprisingly, at short incubation times both Aβ and glutamate decreased NO production in retinal
neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by Aβ and glutamate cause inhibition
rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by Aβ or glutamate is not related
to increased NO production. On the other hand, considering the role of NO in long term potentiation and synaptic plasticity,
the decrease in NO levels instigated by Aβ and glutamate suggests a possible mechanism leading to synaptic failure in AD. 相似文献
11.
12.
Alzheimer’s disease is characterised by the inappropriate death of brain cells and accumulation of the Aβ peptide in the brain.
Thus, it is possible that there are fundamental differences between Alzheimer’s disease patients and healthy individuals in
their abilities to clear Aβ from brain fluid and to protect neurons from Aβ toxicity. In the present study, we examined (1)
the cytotoxicity of Alzheimer’s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer’s
disease and control CSF to protect cells from Aβ toxicity and to promote cell-mediated clearance of Aβ and lastly (3) the
effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer’s disease CSF samples
tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer’s disease CSF samples tested
were less able to protect cells from Aβ-induced toxicity and less efficient at promoting macrophage-like cell uptake when
compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin,
haptoglobin and α2-macroglobulin into CSF protected neuroblastoma cells from Αβ1-42 toxicity and promoted Αβ1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system
of extracellular protein folding quality control that protects against Aβ toxicity and accumulation. 相似文献
13.
Tsuchiya K Tajima H Yamada M Takahashi H Kuwae T Sunaga K Katsube N Ishitani R 《Life sciences》2004,74(26):3245-3258
Overexpression and subsequent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is involved in neuronal apoptosis induced by several stimuli in which GAPDH antisense oligonucleotides specifically block the increment (2 approximately 3 fold) of GAPDH mRNA contents occurring prior to neuronal death. However, these agents do not affect the basal, constitutive mRNA contents. This suggests that there may be distinct gene regulations for GAPDH mRNA expression. Herein, we cloned two types of promoter regions upstream of this gene; viz., #104 (1.02-kb) and #302 (2.46-kb). These fragments were inserted into the pGL3 luciferase reporter system and transiently transfected into cultured cerebellar neurons undergoing cytosine arabinonucleoside-induced apoptosis. The functional analysis of these constructs revealed that #104, but not #302, increased luciferase activity in response to the apoptotic stimulus. Deletion and replacement mutation analysis of the #104 fragment disclosed the promoter core harbored between the 154-bp and 84-bp domains (3.5-fold activity of the control). Furthermore, anti-dementia drugs (such as Cognex and Aricept) markedly depress the expression of this pro-apoptotic GAPDH promoter activity. Interestingly, immunocytochemical examination of human post-mortem materials from patients with Alzheimer's disease revealed nuclear aggregated GAPDH in neurons of the affected brain regions, implying an association with apoptotic cell death. The current findings indicate that induction of the pro-apoptotic protein GAPDH is genetically regulated at the level of promoter activation, and this protein may be an important molecular target for developing anti-apoptotic therapeutic agents in certain neurological illnesses. 相似文献
14.
Lambracht-Washington D Qu BX Fu M Anderson LD Stüve O Eagar TN Rosenberg RN 《Cellular and molecular neurobiology》2011,31(6):867-874
The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides
in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were
immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory
Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune
response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell
proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42
peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune
response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were
immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype
profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal
study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response
and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune
system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective
and safe to treat patients with early AD. 相似文献
15.
Caffeoylquinic acid (CQA) is one of the phenylpropanoids found in a variety of natural resources and foods, such as sweet
potatoes, propolis, and coffee. Previously, we reported that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) has a neuroprotective effect against amyloid-β (Aβ)-induced cell death through the overexpression
of glycolytic enzyme. Additionally, 3,5-di-CQA administration induced the improvement of spatial learning and memory on senescence
accelerated-prone mice (SAMP8). The aim of this study was to investigate whether 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri-CQA), isolated from propolis, shows a neuroprotective effect against Aβ-induced cell death
on human neuroblastoma SH-SY5Y cells. To clarify the possible mechanism, we performed proteomics and real-time RT–PCR as well
as a measurement of the intracellular adenosine triphosphate (ATP) level. These results showed that 3,4,5-tri-CQA attenuated
the cytotoxicity and prevented Aβ-mediated apoptosis. Glycolytic enzymes, phosphoglycerate mutase 1 (PGAM1) and glyceraldehyde-3-phosphate
dehydrogenase (G3PDH) were overexpressed in co-treated cells with both 3,4,5-tri-CQA and Aβ. The mRNA expression of PGAM1,
G3PDH, and phosphoglycerate kinase 1 (PGK1), and intracellular ATP level were also increased in 3,4,5-tri-CQA treated cells.
Taken together the findings in our study suggests that 3,4,5-tri-CQA shows a neuroprotective effect against Aβ-induced cell
death through the upregulation of glycolytic enzyme mRNA as well as ATP production activation. 相似文献
16.
G. Szebenyi G. Morfini M. Young S. Sheridan M. J. McPhaul S. T. Brady 《Journal of neurochemistry》2001,81(S1):76-76
The mechanisms underlying neuronal degeneration in Alzheimer's disease (AD) are very controversial and none more so than whether apoptosis plays a role. Although neurons in AD face a wide assortment of apoptogenic stimuli, the temporal dichotomy between the acuteness of apoptosis vs. the chronicity of AD suggests that apoptosis should be extremely rare in AD. In this regard, survival factor(s) must be involved. In this study, we investigated Bcl-w, a pro-survival member of the Bcl-2 family. Although expressed at low levels in brains of control cases, Bcl-w is significantly up-regulated in AD as shown by both immunocytochemistry and immunoblot analysis. Astonishingly, increased Bcl-w was found to be associated with neurofibrillary pathologies in AD, which was further demonstrated by an EM study. Since neuronal death in AD is thought to be triggered by increased production of amyloid-β (Aβ), it was interesting to find that exposure of human M17 neuroblastoma cells to Aβ1–42 (1 n m −10 μ m ) dramatically up-regulates Bcl-w protein levels. Such increases may be a protective response that attenuates apoptotic processes. Consistent with this, transfected M17 cells overexpressing Bcl-w were protected from both STS-induced and Aβ-induced apoptosis compared to vector-transfected controls. Notably, both tau phosphorylation and p38 is inhibited in Bcl-w transfected cells which may contribute to the neuroprotective role of Bcl-w. Taken together, these set of in vitro and in vivo results suggest that Bcl-w plays an important protective role in neurons in the AD brain. 相似文献
17.
Elongation of Outer Transmembrane Domain Alters Function of Miniature K+ Channel Kcv 总被引:11,自引:0,他引:11
Okada Y Shimizu T Maeno E Tanabe S Wang X Takahashi N 《The Journal of membrane biology》2006,209(1):21-29
Apoptosis is an essential process in organ development, tissue homeostasis, somatic cell turnover, and the pathogenesis of
degenerative diseases. Apoptotic cell death occurs in response to a variety of stimuli in physiological and pathological circumstances.
Efflux of K+ and Cl− leads to apoptotic volume decrease (AVD) of the cell. Both mitochondrion-mediated intrinsic, and death receptor-mediated
extrinsic, apoptotic stimuli have been reported to rapidly activate Cl− conductances in a large variety of cell types. In epithelial cells and cardiomyocytes, the AVD-inducing anion channel was
recently determined to be the volume-sensitive outwardly rectifying (VSOR) Cl− channel which is usually activated by swelling under non-apoptotic conditions. Blocking the VSOR Cl− channel prevented cell death in not only epithelial and cardiac cells, but also other cell types, by inhibiting the induction
of AVD and subsequent apoptotic events. Ischemia-reperfusion-induced apoptotic death in cardiomyocytes and brain neurons was
also prevented by Cl− channel blockers. Furthermore, cancer cell apoptosis induced by the anti-cancer drug cisplatin was recently found to be associated
with augmented activity of the VSOR Cl− channel and to be inhibited by a Cl− channel blocker. The apoptosis-inducing VSOR Cl− channel is distinct from ClC-3 and its molecular identity remains to be determined. 相似文献
18.
V. V. Kolobov T. V. Davydova I. A. Zakharova V. Yu. Gorbatov V. G. Fomina 《Molecular Biology》2012,46(5):678-686
The rat model of Alzheimer’s disease including injection of neurotoxic fragment of β-amyloid protein Aβ25–35 into giant-cell nuclei basalis of Meynert was used for experiments. We have investigated the influence of glutamate antibodies administered intranasally in a dose of 300 μg/kg after 1 h of the mentioned alteration on the level of expression of Dffb mRNA. Dffb gene codes caspase-dependent DNase, which participates in the internucleosomal fragmentation of genome DNA during apoptosis. On the third day after the injection of Aβ25–35, we obtained a significant decrease in Dffb gene expression in the prefrontal cortex (37% decrease) and hippocampus (62% decrease) in the group of experimental animals compared to the control group. In the hypothalamus, there were no such differences. Seemingly, the repressing action of glutamate antibodies on the mRNA expression of the Dffb gene reflects the stabilization of processes that take place in the brain cells during experimental Alzheimer’s disease; meanwhile, the intensity of the apoptotic death of neurons and glial cells decreases. 相似文献
19.
We have investigated the neuroprotective effect of sesaminol glucosides (SG) in SK-N-SH cells. SG prevented apoptotic cell
death induced by Aβ25–35. In parallel, SK-N-SH cells exposed to Aβ25–35 underwent oxidative stress as shown by the elevated level of intracellular ROS, lipid peroxidation, and 8-hydroxy-2′-deoxyguanosine
(8-OHdG) formation, which were effectively suppressed by SG treatment. Furthermore, SG reversed the activities of catalase
and glutathione peroxidase, and restored intracellular GSH levels in Aβ25–35 challenged SK-N-SH cells. In addition, SG inhibited not only Aβ25–35-induced apoptotic features including cleavage of poly(ADP-ribose) polymerase, activation of caspase-3, and activation of
caspase-9, but also elevated Bax/Bcl-2 ratio in SK-N-SH cells treated with Aβ25–35. It was also observed that Aβ25–35 stimulated the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular protein regulated protein
kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAP kinase. SG inhibited phosphorylation of the JNK, ERK and p38 MAP
kinase. These results suggest that SG has a protective effect against Aβ25–35-induced neuronal apoptosis, possibly through scavenging oxidative stress and regulating MAPKs signaling pathways. 相似文献
20.
Ranjan P Boss JM 《Apoptosis : an international journal on programmed cell death》2006,11(10):1837-1849
The CCAAT enhancer binding protein-β (C/EBPβ) is a critical regulator of many cellular processes. Exposure of C/EBPβ-deficient
fibroblasts to tumor necrosis factor-α (TNF) resulted in their death due to apoptosis. While, the expression of Bad, Bcl-2,
Bcl-x, CAS, and hILP/XIAP, as well as the nuclear translocation of NF-κB was normal in C/EBPβ-deficient cells, induction of
manganous superoxide dismutase (MnSOD) gene did not occur. Ectopic expression of C/EBPβ in C/EBPβ–deficient fibroblasts prevented
TNF-induced apoptosis. C/EBPβ complemented cells were able to induce MnSOD in response to TNF, ruling out the possibilities
that C/EBPβ could render protection by regulating early apoptotic gene expression and/or NF-κB p65 expression. Moreover, C/EBPβ-deficient
cells stably transfected with an MnSOD expression vector bypassed the requirement of C/EBPβ in protection against TNF-induced
cell death, suggesting that C/EBPβ protects TNF-induced apoptotic cell death through its role in activating MnSOD expression.
Mechanistically, C/EBPβ was required for induced NF-κB p65 binding to MnSOD’s intronic TNF response element and indispensable
for histone acetylation of the element in response to TNF. These results suggest a role for C/EBPβ in MnSOD regulation through
remodeling of local chromatin structure.
This work was supported by a grant from the National Institutes of Health, CA96810. 相似文献