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1

Amyloid-Beta at the crossroad of neurodegeneration and neuroinflammation

100%
Czapski G. A.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
An increasing body of evidence demonstrated that oligomers of Amyloid beta (Aβ) are the most toxic form, which is responsible for neuronal dysfunction, neurodegeneration and cognitive impairment in Alzheimer’s disease (AD). Among many pathological alterations evoked by Aβ, modulation of innate mechanisms of inflammatory response seems to be especially important, in both early and late stages of AD. Misfolded Aβ peptides stimulate Toll-like receptors and activate phagocytic activity of microglia, leading to clearance of Aβ. However, prolonged activation may divert immune system from its beneficial functions and evoke sustained release of inflammatory mediators and reactive oxygen species responsible for degeneration of neurons. On the other hand, inflammation-related processes promote Aβ formation and another AD-related pathological alterations, leading to initiation of self-propagating cycle. Our studies focused on the role of cyclin-dependent kinase 5 in molecular mechanisms of toxicity of Aβ. Experiments on mouse model of AD demonstrated that this kinase may regulate expression of inflammation-related genes in the brain. Depending on age, disease stage and other environmental conditions, neuroinflammatory processes may be beneficial, promoting neuroprotection and neuroregeneration, or can result in neuronal damage. The data suggest that modulation of immune system is a promising protective strategy in AD. This study was supported by The National Science Centre Grant 2011/03/B/NZ3/04549
2

Inhibition of 12-lipoxygenase protects against amyloid beta peptides-evoked toxicity, memory impairment and alteration of locomotor activity

51%
Czapski G. A., Cakala M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
The pro-infl ammatory enzyme 12/15-lipoxygenase (12/15-LOX) is upregulated in Alzheimerís disease (AD), but the role of the enzyme in a amyloid beta (AB)-evoked toxicity is not fully understood. Its pro-oxidative activity may contribute to the pathophysiology of AD. The aim of this study was to analyze the expression and activity of 12-LOX in animal model of AD. The role of 12-LOX in AB42-evoked memory impairment and locomotory activity and the effect of systemic infl ammation on AB-dependent alterations were also studied. Then the relationship between AB concentration and 12-LOX was examined using PC12 cells transfected with human wild-type and mutant AB precursor protein (APP) gene. Twelve-month-old C57Bl6 mice were injected with AB42 (1 nmol, icv) alone or simultaneously with lipopolysaccharide (LPS; 1 mg/kg, ip). Some mice received 12-LOX inhibitor, beicalein (10 mg/kg, ip). Our results indicated that AB signifi cantly increased 12-LOX expression and activity in hippocampus. Beicalein effectively prevented AB-induced 12-LOX activation and protected mice against memory defi cit and locomotory disturbances. In vitro studies demonstrated the signifi cant relationship between AB level and 12-LOX expression, oxidative stress and NF-κB activation. Beicalein protected PC12 cells against NF-κB nuclear translocation. Our data indicated that 12-LOX is involved in AB toxicity. Beicalein protected mice against memory defi cit and locomotory disturbances, suggesting that 12/15-LOX inhibitors may provide new therapeutic opportunities in treatment of AD. Supported by MS&HE scientifi c network 28/E-32/SN-0053/2007
3

alpha-Synuclein stimulates nitric oxide synthase (NOS) by activation of NMDA receptor

51%
Adamczyk A., Czapski G. A., Kazmierczak A., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
4

The role of Cdk5/p35 and cPLA2/LOX in neuroinflammation and neurodegeneration

51%
Czapski G. A., Cakala M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Cyclin dependent kinase 5 (Cdk5) is implicated in the pathomechanism of Alzheimer’s disease (AD), as a kinase responsible for hyperphosphorylation of tau protein and aberrant metabolism of Amyloid β (Aβ) precursor protein. The previous data indicated the involvement of Cdk5 in regulation of cytosolic phospholipase A2 (cPLA2) gene, but its precise function is not fully understood. In our studies, we analyzed in animal AD model the role of Cdk5 in neuroinflammation and in regulation of cPLA2/lipoxygenase (LOX) pathway. Our data indicated an increase in gene expression for cPLA2, 5-LOX and 12/15-LOX in the hippocampus during the systemic inflammation. In parallel, we observed an increase in expression of the Cdk5 activating protein – Cdk5r1 (p35), suggesting the enhancement of Cdk5 activity and its possible role, as the regulatory factor. Using mouse AD model we demonstrated enhancement of 12-LOX expression and activity and cognitive impairment, which was prevented by 12-LOX inhibitor. Our results demonstrated the important role of inflammatory reaction in cognitive impairment. The relationship between Cdk5 and cPLA2/ LOX during neuroinflammation may have a significant implication for the pathomechanism of AD, and presents Cdk5/p35 as the promising target for improvement of AD therapy. This study was funded by grant from The National Science Centre 2011/03/B/NZ3/04549.
5

NAC peptide evoked oxidative stress leads to p53 mediated apoptosis

51%
Kazmierczak A., Czapski G. A., Adamczyk A., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
The non-Aβ component of Alzheimer’s disease (AD) amyloid (NAC) is a highly amyloidogenic peptide consisting of 35 amino acids which was first identified associated with senile plaques in AD brain. It is a fragment of the presynaptic protein alpha-synuclein and, as such, it is implicated in the etiologies of both Alzheimer’s and Parkinson’s (PD) disease. However the molecular mechanisms of NAC toxicity is not fully understood. Our present study focused on the role of oxidative stress mediated p53 pathway in apoptotic cell death evoked by NAC peptide. Here we found that exposure of PC12 cells to exogenous NAC peptide (10 µM) enhanced free radical generation, induced mitochondria dysfunction and cell death. We also observed free radicals-dependent enhancement of Tp53 gene expression after NAC treatment. The inhibition of p53 by pifithrin significantly protected PC12 cells against NAC peptide - evoked mitochondria failure and death. In addition, exposure to NAC peptide resulted in the higher expression of cyclin-dependent kinase 5 (Cdk5), one of the enzymes responsible for p53 phosphorylation and activation. Concomitantly, we observed the increase of expression of Cdk5r1 and Cdk5r2 genes, coding p35 and p39 peptides, that are essential co-factors in regulation of Cdk5 activity. Moreover, the specific Cdk5 inhibitor (BML-259, 10µM) protected large population of cells against NAC-evoked cell death. Our findings indicate that NAC peptide exerts its toxic effect by activation of p53/Cdk5 - dependent apoptotic signaling pathway. This study was supported by MSHE Grant NN 401024236 and statutory theme no 7.
6
Content available remote

Non-Abeta component of Alzheimer's disease amyloid and amyloid beta peptides evoked poly(ADP-ribose) polymerase-dependent release of apoptosis-inducing factor from rat brain mitochondria

51%
Adamczyk A., Czapski G. A., Jesko H., Strosznajder R. P.
Journal of Physiology and Pharmacology. Supplement
|
2005
|
tom 56
|
nr 2
5-13
Amyloid beta peptide (Aß) and non-Aß component of Alzheimer’s disease amyloid (NAC) are involved in pathomechanism of Alzheimer's Disease (AD) and are deposited in the AD brain in the form of senile plaques. However, the mechanism of their neurotoxicity is not fully understood. In this study the sequence of events involved in NAC and Aß peptides evoked toxicity was investigated in brain slices, synaptosomes and in subcellular fractions. Radio-, immunochemical, spectrophotometrical methods and DNA electrophoresis were used in this study. Our data indicated that Aß 1-40 (25 µM) and NAC (10 µM) peptides induced liberation of free radicals and massive DNA damage that lead to activation of DNA bound enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In consequence of these processes apoptosis-inducing factor (AIF) was released from mitochondria and was translocated to nucleus. The inhibitor of PARP, 3-aminobenzamide significantly decreased AIF release from mitochondria and its translocation. Both peptides under the investigated conditions had no effect on caspase-3 activity. Our data indicated that Aß and NAC peptides stimulate AIF-dependent apoptotic pathway that seems to be caspase independent process. The inhibition of PARP-1 may protect the brain against Aß and NAC toxicity.
7

Inflammation related apoptosis can be prevented by inhibition of nitric oxide synthesis

51%
Czapski G. A., Cakala M., Gajkowska B., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
8

Sphingosine kinase and glycogen synthase kinase-3Beta in molecular mechanism of Alzheimer’s amyloid Beta toxicity

51%
Czapski G. A., Gassowska M., Wilkaniec A., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Alterations of phosphorylation-dephosphorylation processes play a crucial role in the pathomechanism of Alzheimer’s disease (AD). They affect signaling cascades and lead to hyperphosphorylation of tau protein. Glycogen synthase kinase 3β (Gsk-3β) is the main tau-kinase; however, little is known about the role of sphingolipid pathway in its regulation. Alteration of sphingolipid biostat may be an early event in etiopathology of AD. The question arises, if the sphingosine kinase (Sphk), a key enzyme in sphingolipid pathway, regulates Gsk-3β? We analyzed acute effects of exogenous amyloid β (Aβ) oligomers in PC12 cells, and prolonged exposition to endogenous Aβ in PC12 cells stably expressing human Swedish mutant APPsw gene. Our data indicated that in cells subjected to exogenous Aβ expression of Sphk1 and phosphorylation of Gsk-3β at Ser9 were enhanced, what could be considered as a component of protective mechanism. However, prolonged liberation of Aβ in APPsw cells evoked inhibition of Sphk1 expression, activation of Gsk-3β and death of significant population of cells. Consequently, an inhibitor of Sphk1 also reduced cell viability. Our data suggest the existence of specific relationship between Sphk1 and Gsk-3β and indicate their role in alteration of cell function and survival. The study was supported by MSHE Grant N401 587040.
9

The role of glycogen synthase kinase-3beta in alpha-synuclein-evoked tau phosphorylation

51%
Gassowska M., Czapski G. A., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Hyperphosphorylation of tau is involved in the pathomechanism of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Recent studies suggested the significance of alpha-synuclein (ASN) in tau phosphorylation, however, the molecular mechanism responsible for ASN-mediated tau modification remains to be elucidated. In this study, we investigated the role of extracellular ASN in tau phosphorylation in PC12 dopaminergic cells and the involvement of glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in ASN-induced tau modification and cell death. We found that exogenously added ASN (10 µM) stimulates the phosphorylation of tau at Ser396 in PC12 cells. A specific GSK-3β inhibitor (SB-216763) prevented ASN-evoked tau hyperphosphorylation without effect of CDK5 inhibitors. Furthermore, we found that ASN enhanced of GSK-3β protein level and activity. Cell viability determined by MTT assay and Hoechst 33258 staining showed that ASN induced PC12 cell death that presented typical apoptotic morphology. SB-216763 prevented apoptotic cell death evoked by ASN. Concluding, extracellular ASN is involved in GSK-3β-dependent tau modulation and its proapoptotic effect might be mediated at least in part by GSK-3β-catalysed tau phosphorylation and cytoskeleton destabilisation. Supported by a grant from The National Science Centre 2012/05/B/NZ3/02047.
10

Extracellular alpha-synuclein contributes to gsk-3beta-dependent Tau phosphorylation in PC12 dopaminergic cells: Its role in pathomechanism of Parkinson’s disease

51%
Gassowska M., Czapski G. A., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
alpha-Synuclein (ASN) play important role in pathogenesis of Parkinson’s disease (PD) and other neurodegenerative disorders. Novel and most interesting data showed elevated tauopathy in PD and suggested relationship between ASN and Tau protein. However, the mechanism of ASN-evoked Tau protein modification is not fully elucidated. In this study, we investigated the role of glycogen synthase kinase-3β (Gsk-3β) and cyclin-dependent kinase 5 (Cdk5) in ASN-evoked Tau modification in dopaminergic PC12 cells. We used real-time quantitative PCR (qRT-PCR) analysis to assess Gsk3β gene expression and Western blot technique to analyse protein phosphorylation. The presence of apoptotic cells was assessed by Hoechst 33258 fluorescent staining, and cell viability was determined by the 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Our data showed that exogenously added ASN (10 μM) increases Tau phosphorylation on Ser396 and specific Gsk-3β inhibitor (SB-216763, 10 µM) opposite to Cdk5 inhibitor protects cells against Tau hyperphosphorylation. Western blot analysis showed that ASN affected Gsk-3β via increasing of protein level and activation of this enzyme. From immunochemical studies, was found that ASN treatment leads to significant increase in GSK-3β immunoreactivity by about 20%. GSK-3β activity evaluated by its phosphorylation status assay showed that ASN significantly increased the phosphorylation of this enzyme at Tyr216 with parallel decrease in phosphorylation at Ser9, indicative of stimulation of GSK-3β activity. ASN-induced apoptotic processes leads to decrease of PC12 cells viability, the apoptotic cells determined by phase contrast together with Hoechst 33258 fluorescent staining, indicated significantly increase of apoptosis in the presence of ASN. SB-216763 prevented ASN-induced cytotoxicity and enhanced PC12 cell viability. In conclusion, all these findings suggested that extracellular ASN is involved in Gsk-3β-dependent Tau modulation and its proapoptotic effect might be mediated at least in part by the Gsk-3β catalysed Tau hyperphosphorylation and impairment of cytoskeleton stability. GSK-3β inhibitors may offer promising tool against ASN-induced Tau modification and cytotoxicity in neurodegenerative disorders. Supported by statutory theme 9.
11

Pharmacological inhibition of cyclindependent kinase 5 modifies gene expression in mouse model of amyloid beta toxicity

51%
Czapski G. A., Wilkaniec A., Gassowska M., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: The prominent features of Alzheimer’s disease (AD) are accumulation of amyloid beta (Aβ) oligomers and neuroinflammatory processes. Previous data demonstrated that activation of cyclin-dependent kinase 5 (Cdk5) may be essential for pathology of AD and other neurodegenerative disorders. In this study we focused on the role of Cdk5 in controlling gene expression in the brain in experimental model of AD as well as during systemic inflammatory reaction (SIR) METHODS: Alzheimer’s Aβ toxicity and SIR were induced in mice by intracerebroventricular injection of Aβ1-42 oligomers and intraperitoneal injection of lipopolysaccharide (LPS), respectively. Roscovitine, the inhibitor of Cdk5, was administered intraperitoneally. RESULTS: Both Aβ and LPS induced an increase in Cdk5 activity in hippocampus, as evidenced by augmented formation of Cdk5 activator, p25, and enhanced phosphorylation of Cdk5. In concordance, Cdk5-related increase in phosphorylation of Gsk-3β (Ser9) and MAP tau (Ser396) was found. Moreover, we found Cdk5-dependent phosphorylation of ERK1/2 (Thr183/Tyr185) and MEF2A (Ser406), that may negatively modulate activity of transcription factors and in consequence the expression of various genes, i.a. those related to prosurvival pathways. Aβ and LPS injection evoked rapid activation of inflammation-related genes in hippocampus, Nos2, Tnfa, Il1b, Il6, Il10, whereas inhibition of Cdk5 with Roscovitine modified the level of micro RNA and augmented Aβ- and LPS-induced changes in mRNA level for several inflammationrelated genes. CONCLUSIONS: Cdk5 participates in regulation of gene expression in Aβ toxicity and in SIR. Our data suggest that modulation of Cdk5 activity may be prospective strategy for protection in neurodegenerative disorders. This study was supported by The National Science Centre grant 2011/03/B/NZ3/04549.
12

The role of cyclin-dependent kinase 5 in regulating early inflammatory signaling in the mouse brain during amyloid beta toxicity

51%
Czapski G. A., Wilkaniec A., Gassowska-Dobrowolska M., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Cyclin-dependent kinase 5 (Cdk5) belongs to the family of serine/threonine kinases and plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Moreover, our recent study demonstrated the involvement of Cdk5 in regulating inflammatory processes in the brain during peripheral activation of immune system. However, the relationship between AD, Cdk5 and neuroinflammation is poorly understood. AIM(S): The aim of this study was to investigate the involvement of Cdk5 in regulating neuroinflammation in mouse model of amyloid beta (Aβ) toxicity METHOD(S): Here, we used the experimental model, based on single intracerebroventricular injection of Aβ1‑42 oligomers, enabling the production of Alzheimer-like behavioral abnormalities and resembling some molecular events occurring during early stage of AD. The brain tissue was analyzed up to 35 days post-injection. The role of Cdk5 in inflammatory process activation was evaluated using the pharmacological Cdk5 inhibitor roscovitine. RESULTS: Our results demonstrated that injection of Aβ1‑42 oligomers induces long‑lasting activation of microglia and astrocytes in hippocampus. Analysis of mRNA level for inflammation‑related genes (e.g. Tnf‑α, IL‑1β, IL‑6) showed rapid rise as early as 3 h after injection of Aβ1‑42. Notably, injection of scrambled Aβ1‑42 had no effect on expression of inflammatory mediators. Furthermore, Aβ1‑42 promotes p25 generation, indicative of increased Cdk5 activity. Importantly, inhibition of Cdk5 with roscovitine significantly reduced gene expression and/or protein level of Tnf‑α, IL‑1β, IL‑6, IL‑10 and Nos2. CONCLUSIONS: Our data indicated that Cdk5 plays an important role in Aβ toxicity via controlling brain inflammatory processes. These findings provide important new insights into the molecular mechanisms linking neuroinflammation with the pathogenesis of Alzheimer’s disease. FINANCIAL SUPPORT: This study was supported by The NCN Grant 2011/03/B/NZ3/04549.
13

Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in PC12 cells

45%
Adamczyk A., Gasowska M., Wilkaniec A., Cieslik M., Czapski G. A.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
α-Synuclein (ASN) secreted from neurons into the extracellular space affects the homeostasis of neighboring cells, but the pathophysiology of extracellular ASN remains largely unknown. The aim of the present study was to analyze the role of cyclin dependent kinase 5 (Cdk5) in molecular mechanism of extracellular ASN toxicity. We found that exogenously applied ASN evoked apoptotic cell death in a significant population of dopaminergic PC12 cells. ASN induced rapid and long-lasting calcium influx and activation of calciumdependent enzymes, including caspase-3, nitric oxide synthase and calpain. ASN-induced calpain activation leads to cleavage of Cdk5 activator p35, and subsequently to formation of p25 and Cdk5 overactivation. Moreover, we showed that exposure of PC12 cells to ASN increased Cdk5 activity by enhancement of its phosphorylation at Tyr15. Calpeptin, an inhibitor of calpains, and inhibitors of Cdk5, Roscovitine and BML-259, prevented ASN-evoked apoptosis and cell death, indicating the involvement of Cdk5 in mechanism of ASN toxicity. Our data showed that alterations in calcium homeostasis and modulation of calcium-dependent enzymes by extracellular ASN may contribute to the early stages of pathogenesis in Parkinson’s disease and other synucleinopathies.Supported by a grant from The National Science Centre 2012/05/B/NZ3/02047.
14

P2X7 receptor mediates extracellular alpha-synuclein-induced mitochondrial dysfunction in neuroblastoma SH-SY5Y cells

45%
Wilkaniec A., Lenkiewicz A. M., Czapski G. A., Sulkowski G., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: α‑Synuclein (ASN) accumulation and mitochondrial dysfunction are central to the pathogenesis of most forms of Parkinson’s disease (PD) and appear to intersect, but how the two are related to each other has remained elusive. Recent research emphasised the important role of purinergic signalling dysfunction in PD. While the significant role of purinergic P2 family receptors in mitochondrial dysfunction is well known, the interaction of extracellular soluble ASN with purinergic receptors as well as the involvement of this interaction on mitochondria are not yet studied. AIM(S): The aim of this study was to investigate the effect of ASN on P2 purinergic signalling and the involvement of purinergic receptors in mitochondrial dysfunction. METHOD(S): As a research model we used neuroblastoma SH-SY5Y cell line as well as rat synaptoneurosomes treated with exogenous soluble ASN. The experiments were performed using spectrofluorometric, radiochemical and immunochemical methods. RESULTS: We found that exogenous ASN directly interacts with purinergic P2X7 receptor leading to its activation and intracellular free calcium mobilization in neuronal cells and nerve endings. Activation of P2X7 receptors leads to pannexin 1 recruitment and increased ATP release. Furthermore, ASN treatment induced mitochondrial dysfunction: changes in mitochondrial redox state, decrease in mitochondria membrane potential and elevation of mitochondrial superoxide production. This resulted in decreased synthesis of ATP and ultimately cell death. Importantly, treatment with non-selective (PPADS) or selective (AZ 11645373) P2X7 antagonist reversed the ASN-induced mitochondrial damage and prevented SH-SY5Y cells death. CONCLUSIONS: Our data indicated that P2X7 receptor activation is responsible for ASN-induced mitochondrial dysfunction. Thus, interference with P2X7 signalling seems to be a promising strategy for the prevention or therapy of PD and other neurodegenerative disorders. FINANCIAL SUPPORT: Supported by the NSC grant 2013/09/D/NZ3/0135.
15

Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in PC12 cells

45%
Adamczyk A., Gassowska M., Wilkaniec A., Cieslik M., Czapski G. A.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
16

Polymorphism of glycogen synthase kinase 3 Beta and cyclindependent kinase 5 genes in early and late onset Alzheimers disease

39%
Niwinska J. M., Markiewicz P., Styczynska M., Czapski G. A., Barcikowska M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
Alzheimerís disease (AD) is the main cause of dementia in the elderly. Over-activation of Glycogen Synthase Kinase 3 beta and Cyclin-Dependent Kinase 5 has been implicated in the aberrant phosphorylation of tau ñ the major component of the neurofi brillary tangles, which besides deposits of amyloid β are pathological hallmarks of AD. In this study we assessed the association between single nucleotide polymorphism (SNP) in those kinases genes and the risk of early (EOAD) and late onset (LOAD) Alzheimerís disease. TaqMan SNP genotyping assay or polymerase chain reactionrestriction fragments length polymorphism (PCR-RFLP) assay were used to genotype 4 SNP sites in 198 Polish LOAD cases, 71 EOAD cases and 104 controls. The distribution of genotypes in rs334558 SNP in GSK3β gene signifi cantly differed between patients with late onset AD and aged related, healthy control group. No signifi cant association between rs9278, rs2069454 and rs2069442 SNPs in CDK5 gene and AD was found and none of the examined alleles can be considered now as a genetic risk factor in AD in Polish population. The analysis of environmental factors showed higher serum level of total cholesterol and lower LDL (low density lipoprotein) level in EOAD and LOAD groups compared to control group. Moreover lower level of vitamin B12 and higher homocysteine level were observed only in LOAD group compared to controls. This study was supported MS&HE scientifi c network 28/E-32/SN0053/2007
17

Association between plasma biomarkers, CDK5 polymorphism and the risk of Alzheimer's disease

39%
Czapski G. A., Maruszak A., Styczynska M., Zekanowski C., Safranow K., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2012
|
tom 72
|
nr 4
In this study we evaluated biochemical blood serum parameters and the association of Cyclin-dependent kinase 5 (CDK5) gene polymorphisms with the risk of Alzheimer's disease (AD) in the Polish population. We observed an elevated total cholesterol, low-density lipoproteins (LDL) and homocysteine levels and lower concentrations of high-density lipoproteins (HDL) and vitamin B12 in AD patients. However, the analyzed CDK5 polymorphisms were not associated with the biochemical parameters. Moreover, we found no association between the studied polymorphisms and the risk of AD in the Polish population. The meta-analysis of previously published and current study was performed. In conclusion, our study demonstrated that alteration of cholesterol, LDL, HDL, homocysteine and B12 concentration may be an important factor in pathogenesis of AD.
18

Perinatal exposure to lead (Pb) affects the function of Tau and Tau-kinases in the rat brain

39%
Gassowska M., Baranowska-Bosiacka I., Moczydlowska J., Czapski G. A., Falkowska A., Struzynska L., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Hyperphosphorylation of Tau is involved in the pathomechanism of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Epidemiological data suggest the significance of early life exposure to lead (Pb) in etiology of disorders affecting brain function. However, the precise mechanisms by which Pb exerts neurotoxic effects are not fully elucidated. In this study, we investigated the effect of perinatal exposure to Pb on Tau pathology in selected rat brain structures: forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the ultrastructural alterations in these regions. Furthermore, the involvement of two major Tau-kinases: glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in Pb-induced Tau modification was analysed. RESULTS: Our data revealed that pre- and neonatal exposure of rats to Pb (concentration in rat offspring’s blood below a ‘safe level’) evoked significant increase in the phosphorylation of Tau at Ser396 with parallel rise in the level of total Tau protein in FC and C. Moreover, in these brain structures, GSK-3β activity was increased by phosphorylation of a tyrosine residue – Tyr-216. However, GSK3β phosphorylation on serine residue, Ser-9 was unchanged. Parallel with GSK-3β activation we observed increase of total GSK-3β level in FC from rats subjected to Pb. In Pb-treated cerebellum we showed calpain-dependent cleavage of CDK5-activating protein p35 leading to formation of p25 and CDK5 overactivation. Molecular alterations were accompanied by pathological changes in ultrastructure of all examined brain structures from rats subjected to Pb. CONCLUSION: Perinatal exposure to lead induces Tau modification in the rat cortex and cerebellum. We suggest that its neurotoxic effect might be mediated, at least in part, by GSK-3β and CDK5- catalysed Tau hyperphosphorylation, leading to impairment of cytoskeleton stability. Supported from MMRC statutory theme 8.
19

The role of cyclin-dependent kinase 5 in pathomechanism of Alzheimer’s disease

39%
Czapski G. A., Maruszak A., Styczynska M., Zekanowski C., Safranow K., Bialopiotrowicz E., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Alteration of Amyloid Precursor Protein (APP) processing, leading to overproduction of Amyloid beta (Ab), and hyperphosphorylation of Microtubule-Associated Protein (MAP) tau remain in the center of pathomechanism of Alzheimer’s disease (AD). The recent data indicated that oligomeric form of Aβ is responsible for memory impairment in AD. Also deregulation of protein phosphorylation processes plays an important role in AD pathology. Cyclin-Dependent Kinase 5 (CDK5) is responsible for aberrant phosphorylation of both MAP tau and APP. Moreover, CDK5 may also phosphorylate other proteins potentially involved in AD pathogenesis, i.a. Glycogen Synthase Kinase-3b (GSK-3b), NMDAR, p53. The aim of the present study was to analyze the participation of CDK5 in cell death processes occurring in PC12 cells overexpressing APP. As a model, we used cells transfected with human wild-type APP (APPwt) and human APP with Swedish mutation (APPsw). Real-time PCR and Western blotting were used for analysis of expression and phosphorylation of CDK5, CDK5R1, CDK5R2, GSK-3β. Cytotoxicity was evaluated by MTT and LDH tests. To determine the role of CDK5 in AD patients, the association of human CDK5 gene with AD risk was analyzed. Our data demonstrated enhanced cell death and cell cycle disturbances in PC12 cells transfected with APP gene, comparing to control PC12 cells. Real-time PCR analysis indicated increased level of mRNA for CDK5 gene in APPsw cells. Significantly decreased phosphorylation of CDK5 on Tyr15 was observed in APPwt and APPsw cells, what can be responsible for lowering of Cdk5 activity. Moreover, Cdk5-dependent phosphorylation of GSK-3β on Ser9 was also decreased, what can be responsible for GSK-3β activation, hyperphosphorylation of MAP tau and alteration of cell function. Our genetic analysis indicated that there is no association between polymorphism of CDK5 gene and the risk of AD in investigated Polish population (178 healthy controls, 71 EOAD and 204 LOAD cases). Significant differences in serum level of cholesterol, LDL, vitamin B12 and homocysteine between AD patients and healthy controls were found, but there was no association of tested CDK5 genotypes with biochemical parameters. These results indicated the important role of CDK5 - GSK-3β interplay in pathomechanism of AD. This study was supported by MSHE Grant N N401 014635
20

Prenatal exposure to valproic acid leads to behavioral alterations and defects of synaptic proteins in the hippocampus of adolescent rats

39%
Adamczyk A., Gassowska-Dobrowolska M., Cieslik M., Czapski G. A., Jesko H., Gewartowska M., Frontczak-Baniewicz M.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
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nr Suppl.1
Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases characterized by impairment in communication and social interaction along with stereotyped or repetitive behaviors. Multiple studies have highlighted the involvement of synaptic proteins in the pathogenesis of ASDs. AIM(S): The aim of this study was to investigate the effect of fetal exposure to valproic acid (VPA) – a rodent model of environmentally triggered autism – on behavioral phenotype as well as gene expression of autism-associated synaptic proteins and synapse morphology in the hippocampus of adolescent rats. METHOD(S): Pregnant Wistar rats received a single intraperitoneal injection of VPA (450 mg/kg b.w.) on gestational day 12.5. Ultrasonic vocalization was analyzed in all infant rats at postnatal day (PND) 11 and anxiety‑related behavior in adolescent male offspring. At PND 52, male offspring were decapitated and the hippocampi were isolated. Transmission electron microscopy (TEM), qPCR, and immunoblotting were used to analyze synaptic structure and protein expression. RESULTS: VPA administration during pregnancy disturbed communication in neonatal rats and led to anxiety-like and repetitive behavior in adolescent animals. TEM showed synaptic pathology including nerve endings swelling, blurred and thickened synaptic cleft structure, and disruption of synaptic membranes. Ultrastructural changes were accompanied by increased expression of proteins involved in synaptic vesicle recycling and neurotransmitter release (Synaptobrevin, Synaptophysin, Synapsin‑1) and reduction in presynaptic membrane protein SNAP25 and the postsynaptic density scaffold PSD95. Changes also occurred in the expression of Shank family proteins and neuroligin 3. CONCLUSIONS: Deregulated expression of synaptic proteins could be involved in ASDs via alterations of synaptic structure/function, subsequently contributing to behavioral abnormalities. FINANCIAL SUPPORT: Supported by NSC grant 2017/25/B/NZ4/01969.
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