Wyniki wyszukiwania - Biblioteka Nauki

1

The Alzheimer's ABeta peptide evoked oxidative and metabolic stress in rat hippocampal and cortical neurons

100%

Strosznajder J. B.

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nr 3

2

Cyclic GMP metabolism and its role in brain physiology

63%

Domek-Lopacinska K. , Strosznajder J. B.

Journal of Physiology and Pharmacology. Supplement

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2005

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tom 56

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nr 2

15-34

EN

Cyclic GMP (cGMP) is synthesized by guanylyl cyclase (GC) in response to nitric oxide (NO) and carbon monoxide (CO) or natiuretic peptides (NPs); atrial, brain and C-type (ANP, BNP and CNP). cGMP is degraded by several cGMP-specific phosphodiesterases (PDEs). Guanylate cyclases (GC) are differentiated into: membrane-bound/particulate (pGC) and cytosolic/soluble (sGC). In recent years evidence has accumulated that NO is the main activator of sGC and NO/cGMP plays important role in glutaminergic, cholinergic and dopaminergic signaling pathways. cGMP in the nervous system is involved in long term potentiation and depression (LTP, LTD) suggesting its participation in learning and memory mechanism. cGMP regulates calcium homeostasis and phototransduction. Its level is regulated by PDEs and their specific inhibitors protect cGMP level in cells and are very important from clinical point of view.

3

Role of lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity

51%

Cieslik M. , Strosznajder J. B. , Gajkowska B. , Strosznajder R. P.

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nr 1

EN

The roles of 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the molecular processes evoked by amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70-80 % of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding nontreated with SNP cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies. Supported by MS&HE grant NN40113938 and MRC statutory theme No 7.

4

The role of cyclooxygenases and lipooxygenases in mechanism of amyloid beta toxicity

51%

Cakala M. , Jesko H. , Strosznajder J. B.

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2006

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tom 66

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nr 4

5

Alfa-synukleina w fizjologii i patologii mozgu

51%

Solecka J. , Adamczyk A. , Strosznajder J. B.

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tom 32

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nr 2

343-357

6

alpha-Synuclein and its neurotoxic fragment induce apoptotic pathway in PC 12 cells with diferent amyloid beta load

51%

Kazmierczak A. , Adamczyk A. , Strosznajder J. B.

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2006

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tom 66

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nr 4

7

Effect of myloid Beta peptides on DNA degradation

51%

Zambrzycka A. , Czapski G. , Strosznajder J. B.

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nr 3

8

Expression of poly(ADP-ribose) polymerases in hippocampus during systemic inflammatory response. The role of PARP-1 protein interactions in cognition

51%

Czapski G. , Adamczyk A. , Strosznajder R. P. , Strosznajder J. B.

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nr 1

EN

Poly(ADP-ribosyl)ation is covalent modification of proteins responsible for the alterations of their function. This process is catalyzed by poly(ADP-ribose)polymerases (PARP) family, consisted of 18 isoforms. Among target proteins, there are many DNA-related proteins and PARP-1 itself. In the brain, PARP-1 is responsible for more than 90% of poly(ADP-ribosyl)ation. PARP-1 plays a significant role in regulation of several transcription factors including NF-kB and p53. Our previous data indicated an important impact of PARP-1 in brain ischemia and in systemic inflammatory response (SIR). In this study we have analyzed the expression of PARP family genes in hippocampus of mice subjected to lipopolysaccharide (LPS)- evoked SIR. Moreover, the effect of SIR on PARP-1/PAR protein interaction and on memory function was evaluated. Mice C57BL6 were injected i.p. with LPS (1 mg/kg b.w.) alone or together with PARP inhibitors 3-aminobenzamide (30 mg/kg b.w.). The studies were carried out by using immunochemistry, microarray, real-time RT-PCR, and behavioral analysis. Our data indicated the small effect of SIR on PARP-1 gene expression level, however, expression of genes for PARP-3, -9, -12 and -14 was significantly increased 12 h after LPS administration. The level of PAR in hippocampus was elevated during SIR indicating activation of protein poly(ADP-ribosyl)ation. Moreover, further analysis of LPS-affected genes indicated that among 83 proteins known for their direct interaction with PARP-1, genes for 21 are present in SIR-related interactome, along with several genes for transcription factors and proteins involved in signal transduction. The enhancement of gene expression in hippocampus for several members of PARP family during SIR may be responsible for the alteration of PARPs function, higher level of PAR formation and for the modification of PARP/PAR protein interaction, transcription, cell signaling and memory. Our data indicated that SIR significantly decreases object recognition but has small effect on spatial memory. PARP-1 inhibitor protects against SIR induced molecular alteration in hippocampus and against SIR-evoked cognition impairment. Moreover, PARP-1 inhibitors significantly enhanced spatial memory in LPS treated mice. Our results indicate that inhibition of PARP-1 is a promising protective strategy during overactivation of inflammatory reaction. The role of other PARP family members in SIR is a target of our future investigation.

9

The role of nitric oxide in maturation of the cholinergic system in rat brain

51%

Domek-Lopacinska K. , Kaminska M. , Kopczuk D. , Strosznajder J. B.

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tom 65

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nr 3

10

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.

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nr 1

EN

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

11

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

51%

Adamczyk A. , Czapski G. A. , Kazmierczak A. , Strosznajder J. B.

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2006

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tom 66

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nr 4

12

Effect of amyloid beta peptide on poly[ADP-ribose] polymerase activity in adult and aged rat hippocampus

51%

Strosznajder J. B. , Jesko H. , Strosznajder R. P.

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tom 47

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nr 3

EN

It is suggested that the fibrillar amyloid beta peptide (Abeta) in brain plays a direct role in neurodegeneration in Alzheimer's disease, probably through activation of reactive oxygen species formation. Free radicals and numerous neurotoxins elicit DNA damage that subsequently activates poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30). In this study the effect of neurotoxic fragment (25-35) of full length Abeta peptide on PARP activity in adult and aged rat hippocampus was investigated. In adult (4 month old) rat hippocampus the Abeta 25-35 peptide significantly enhanced PARP activity by about 80% but had no effect on PARP activity in cerebral cortex and in hippocampus from aged (24-27 month old) rats. The effect of Abeta peptide was reduced by half by the nitric oxide synthase inhibitor N-nitro-L-arginine. Stimulation of glutamate receptor(s) itself enhanced PARP activity by about 80% in adult hippocampus. However, Abeta 25-35 did not exert any additional stimulatory effect. These results indicate that Abeta, through NO and probably other free radicals, induces activation of DNA bound PARP activity exclusively in adult but not in aged hippocampus.

13

Expression of alpha-synuclein in different brain parts of adult and aged rats

51%

Adamczyk A. , Solecka J. , Strosznajder J. B.

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2005

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tom 56

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nr 1

EN

The synucleins are a family of presynaptic proteins that are abundant in neurons and include alpha-, ß-, and -synuclein. alpha-Synuclein (ASN) is involved in several neurodegenerative age-related disorders but its relevance in physiological aging is unknown. In the present study we investigated the expression of ASN mRNA and protein in the different brain parts of the adult (4-month-old) and aged (24-month-old) rats by using RT-PCR technique and Western blot, respectively. Our results indicated that mRNA expression and immunoreactivity of ASN is similar in brain cortex, hippocampus and striatum but markedly lower in cerebellum comparing to the other brain parts. Aging lowers ASN mRNA expression in striatum and cerebellum by about 40%. The immunoreactivity of ASN in synaptic plasma membranes (SPM) from aged brain cortex, hippocampus and cerebellum is significantly lower comparing to adult by 39%, 24% and 65%, respectively. ß-synuclein (BSN) was not changed in aged brain comparing to adult. Age-related alteration of ASN may affect the nerve terminals structure and function.

14

Alzheimer’s amyloid beta peptides disturb circadian oscillations of intracellular calcium concentration

45%

Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

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tom 73

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nr 1

EN

It is postulated that disturbances in calcium homeostasis play an important role in pathogenesis of Alzheimer’s disease (AD). Changes of neuronal calcium concentration are responsible for the oxidative stress as well as altered metabolism and production of amyloid-beta peptides (Aβ). Aβ may further exacerbate calcium dysregulation, causing synaptic dysfunction, neurodegeneration and cognitive impairment. Recent data indicate that AD is associated with disturbances of circadian rhythm in the patients. However, till now nothing is known about the molecular mechanisms involved in AD-related circadian clock alterations. In our study we investigated the effect of Aβ peptides on the rhythmic oscillation of cytosolic and mitochondrial calcium levels. To investigate molecular clock mechanisms, the studies we carried out in human primary skin fibroblasts, a previously established experimental model. Our data showed circadian rhythm of calcium ions concentration in cytosol and mitochondria. Moreover we observed circadian oscillation of ROS formation and redox potential. Treatment with Aβ fibrils at the concentration of 0.5 µM disturbed cytosolic calcium oscillations and mitochondrial redox state. Studying mechanisms involved in this phenomenon indicated that Aβ did not affect ER calcium stores, but induced changes of calcium influx mediated by purinergic P2X7 receptor. The specific antagonist of P2X7 receptor Brillant Blue G abolished negative impact of Aβ and restored calcium circadian rhythm. Summarizing, our results indicate that Aβ may play a significant role in disturbances of circadian calcium oscillation, suggesting the importance of this phenomenon in ADrelated changes in biological clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E.

15

Neuroprotective effect of fingolimod and pramipexole in Parkinson's disease animal model

45%

Motyl J. , Przykaza L. , Kosson P. , Boguszewski P. M. , Strosznajder J. B.

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tom 75

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nr Supl.

EN

BACKGROUND AND AIMS: Recently sphingolipids alterations have been shown to play an important role in pathomechanism of neurodegenerative diseases. Our last study indicated suppression of gene expression and activity of sphingosine kinases (Sphk1/2)/ sphingosine-1-phosphate (S1P) synthesis in cellular model of Parkinson’s disease (PD). Moreover, the cytoprotective effect of S1P and its analog Fingolimod (P-FTY720) in this PD model was observed. The fundamental goal of current research was to determine the impact of FTY720 and dopamine D2/D3 receptors agonist – pramipexole (PPX) on death signalling and motor activity in mice PD model. METHODS: Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 40 mg/kg) was administrated ip to adult C57BL/6 mice. FTY720 (1 mg/kg) or PPX (1 mg/kg) was injected ip during 10 days. Then behavioral tests (open field, rota-rod, and pole test) were performed. Midbrain and striatum were used for further studies. The immunochemical, spectrofluorometrical, and QPCR methods were applied. RESULTS: Our results indicated significant reduction in the number of dopaminergic cells in the midbrain of MPTP treated animals. Moreover, in this PD model alterations of Sphk1/2 and Akt kinase mediated signalling were found. It was also detected that gene expression of pro-apoptotic proteins in midbrain cells was activated. FTY720 and PPX protected dopaminergic cells against death as a result of Sphks up-regulation and apoptotic signalling suppression. In behavioural examination, MPTP mice exhibited impaired motor coordination in rota-rod test. Total time spent on the accelerating rota-rod was increased two-fold after FTY720 and PPX administration. We have also observed total distance elongation in animals treated with both above mentioned compounds during open-field test. CONCLUSIONS: In conclusion, this study indicated that FTY720 and PPX contribute to improvement of mice motor activity and they offer opportunities for PD therapy. Supported by NCN grant 2013/09/N/NZ4/02045.

16

The relationship between mitochondria function and circadian clock in peripheral oscillators

45%

Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

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tom 73

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nr 1

EN

Circadian rhythms govern a wide variety of physical, behavioral and metabolic changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. These are controlled by the circadian clock mechanism, where rhythm-generating mechanism is encoded by a transcription-translation feedback loop. Numerous studies have pointed to a cyclic relationship wherein the rhythm impacts metabolic activity and metabolism feeds back to impinge upon the rhythm. Mitochondria play a pivotal role in regulating cellular energy and were shown to be strategically positioned at the intersection between circadian rhythm and cell metabolism. Nevertheless little is known about their function in controlling the circadian rhythm. In our study, we investigated the involvement of circadian clock in mitochondrial function as well as mitochondria-dependent regulation of circadian clock. The study was carried out in primary human fibroblasts, an already established model to investigate molecular clock mechanisms in vitro. We have found that mitochondria activity as well as network activities showed rhythmic changes within 24 hours. Circadian pattern was detected for mitochondrial ROS including superoxide anion production. A significant 24-hour oscillation was found for cellular redox state. Furthermore, mitochondrial ATP levels were rhythmic and the maximum of ATP production paralleled the peak of mitochondrial ROS level and the mitochondrial network formation. Circadian rhythm was also detected for calcium ions concentration. Increase of ATP synthesis as well as changes in calcium and ROS level activated AMP-dependent protein kinase (AMPK). We have found that in primary human fibroblasts AMPK protein level and activity fluctuate in an antiphase relationship with rhythmic ATP production. Summarizing, our data provide the evidence for circadian regulation of mitochondrial dynamics and suggest that changes of mitochondrial activity may directly influence cellular clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E

17

Sphingosine kinase-1, the new target in the neuroprotective effect of fingolimod and pramipexole in Parkinson’s disease animal model

38%

Motyl J. , Wencel P. L. , Przykaza L. , Kosson P. , Boguszewski P. M. , Strosznajder J. B.

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nr Suppl.1

EN

INTRODUCTION: Sphingosine kinase (Sphk1) synthetizing sphingosine-1-phoshate (S1P) is a key enzyme responsible for the regulation of cell fate. Sphk1/S1P could be the attractive target in Parkinson’s disease (PD) neuroprotective therapy. Our previous data showed inhibition of Sphk1 expression/activity in PD in vitro model and indicated neuroprotective effect of S1P analog phospho‑fingolimod (FTY720-P). AIM(S): The aim of current research was to investigate the effect of FTY720 and dopamine D2/D3 receptors agonist – pramipexole (PPX) on Sphk1 dependent molecular pathway(s) in selected parts of the brain and on locomotor activity in PD animal model. METHOD(S): Neurotoxin 1-methyl-4-phenyl-1,2,3,6- -tetrahydropyridine (MPTP, 40 mg/kg) was administrated i.p. to adult C57BL/6 mice. FTY720 (1 mg/kg) or PPX (1 mg/kg) were injected i.p. during 10 days. Behavioral tests (open field, rota-rod) were performed. Midbrain and striatum were separated. The immunochemical, spectrofluorometrical, and QPCR methods were applied. RESULTS: Our data indicated that PD mice exhibited significant loss of dopaminergic nerve terminals within striatum, evaluated by reduced tyrosine hydroxylase immunoreactivity level (TH-IR). Moreover we found the lower level of mRNA/ immunoreactivity and activity of Sphk1 in the midbrain of PD mice. Both FTY720 and PPX significantly increased TH-IR in MPTP mice striatum. FTY720 and PPX protected against MPTP-evoked Sphk1 alterations and significantly elevated pro-survival Akt kinase phosphorylation, which indicated its activation. Subsequently, FTY720 increased BAD protein phosphorylation in MPTP mice midbrain, which may protect cells against BAD-mediated death. Then it was observed that FTY-720 and PPX improved locomotor impairment in PD mice. CONCLUSIONS: Our data indicated the new neuroprotective mechanism of PPX and FTY720 action connected with sphingolipid signaling and demonstrated beneficial properties of these compounds on movement alterations in PD animal model. FINANCIAL SUPPORT: This abstract is financially supported by The National Science Centre grant 2013/09/N/ NZ4/02045.

18

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

38%

Niwinska J. M. , Markiewicz P. , Styczynska M. , Czapski G. A. , Barcikowska M. , Strosznajder J. B.

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nr 1

EN

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

19

Nitric oxide enhances expression and activity of cytosolic phospholipase A2 in PC12 cells with the different amyloid beta load

32%

Chalimoniuk M. , Stolecka A. , Haupmann S. , Schulz K. , Keil U. , Leuner K. , Eckert A. , Muller W. E. , Strosznajder J. B.

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2006

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tom 66

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nr 4

20

Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells

32%

Chalimoniuk M. , Stolecka A. , Cakala M. , Hauptmann S. , Schulz K. , Lipka U. , Leuner K. , Eckert A. , Muller W. E. , Strosznajder J. B.

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tom 54

|

nr 3

EN

Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid β (Aβ) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and γ-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+]i and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Aβ peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.