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1

Effects of myriocin and FTY720 on gene expression of sphingolipid metabolism enzymes in animal model of Alzheimer’s disease

100%
Jesko H., Wencel P. L., Strosznajder R. P.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
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nr Suppl.1
INTRODUCTION: Sphingolipid imbalance has been observed in Alzheimer’s disease (AD) (accumulation of the pro-apoptotic ceramide, and loss of the protective sphingosine-1-phosphate – S1P) being correlated with the progress of neurodegeneration. Deregulated sphingolipid homeostasis may lead to neuronal death. Therefore enzymes regulating sphingolipid metabolism gain attention as highly promising targets in AD research/therapy. AIM(S): We examined the influence of myriocin and FTY720 on gene expression of enzymes metabolizing ceramide/sphingosine-1-phosphate in a mouse transgenic AD model. METHOD(S): mRNAs were measured with real-time PCR in the cerebral cortex of 6-months old FVB mice overexpressing human Aβ precursor protein (APP) treated with myriocin, a ceramide biosynthesis inhibitor, and FTY720 a sphingosine analog and sphingosine-1-phosphate receptor modulator. RESULTS: Myriocin has increased the expression of ceramidases ACER2 and -3, ceramide kinase (CERK), sphingosine kinase 2 (SPHK2) and S1P receptors (S1PR1 and -5) in APP mice. These results suggest a metabolic shift from ceramide towards the survival-promoting ceramide-1-phosphate and S1P. However, both Bcl-2 and Bax were increased, leaving the question open. The mock-transfected animals seemed to respond to treatment with a shift towards ceramide accumulation and dephosphorylation of S1P into sphingosine. FTY720 treatment of APP animals increased mRNA levels of ceramide synthases (CERS2 and 6), SPHK1 and 2, and proteins from Bcl-2 family. CONCLUSIONS: Our results suggest that myriocin and FTY720 treatment may lead to widespread modification of gene expression in the sphingolipid rheostat and signaling pathways, which requires further research to fully understand their mechanisms of action. FINANCIAL SUPPORT: Supported by the National Science Center grant no NCN/15/B/NZ3/01049.
2

The role of sphingosine kinases/sphingosine-1-phosphate in the regulation of alpha-synuclein and amyloid beta precursor protein secretion. Implications for neurodegenerative disorders

100%
Jesko H., Okada T., Nakamura S., Strosznajder R. P.
Acta Neurobiologiae Experimentalis
|
2013
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tom 73
|
nr 1
Sphingolipid deregulation may be an important factor of age-related neuronal stress vulnerability. Current data suggests potential links between sphingosine kinases (SphK1&2), their product sphingosine1-phosphate (S1P) and age-related protein conformation diseases. The aim of this study was to investigate a possible role of SphKs in alpha-synuclein (ASN) and amyloid beta (ABeta) precursor protein (APP) level and secretion. The studies were carried out using human SH-SY5Y neuroblastoma cell line stably transfected with the human gene for α-synuclein (ASNwt). Sphingosine kinase inhibitor (SKI) significantly increased ASN secretion in concentration-dependent manner. S1P also displayed similar influence. Neither compound exerted any significant effect on the ASN protein level. S1P may act via cell surface receptors or as an intracellular second messenger. The similar effect of S1P and SphK inhibitors on ASN secretion may suggest that the regulation of its release is critically dependent on the varied (intra)cellular targets of SphKs and downstream signaling pathways. We have found that stable human ASNwt expression in SH-SY5Y cells caused a three-fold, significant increase of the cellular APP level. In ASN-transfected cells S1P enhanced APP secretion and reduced its intracellular level. This could be linked to the recently reported effect of S1P on secretase beta activity. Inhibition of SphKs significantly decreased APP secretion. In summary our data indicates that endogenous ASN regulates APP level in SH-SY5Y cells and that sphingolipids play a crucial role in the secretion of ASN and APP. These processes may have significant impact on neuronal survival and health.
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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

100%
Adamczyk A., Czapski G. A., Jesko H., Strosznajder R. P.
Journal of Physiology and Pharmacology. Supplement
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2005
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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.
4

The interplay between parkin and alpha‑synuclein; possible implications for the pathogenesis of Parkinson’s disease

100%
Jesko H., Lenkiewicz A. M., Wilkaniec A., Adamczyk A.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr 3
Parkin and alpha‑synuclein (α‑syn) are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Oligomerization/ aggregation and excessive secretion of α‑syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of α‑syn. This is in addition to parkin’s role in counteracting the more distant effects of α‑syn on cellular survival by altering proteasomal, autophagic, and calpain‑mediated protein degradation pathways that can reduce α‑syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena – processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of α‑syn by controlling its post‑translational modifications. On the other hand, recent research has shown that α‑syn oligomers affect the expression, post‑translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross‑talk between parkin and α‑syn in PD. The physical and functional interactions between α‑syn and parkin, which have been incompletely characterized to‑date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the therapy of PD.
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Poly(ADP-ribose) polymerase-1 is a novel nuclear target for cholinergic receptor signaling in the hippocampus

100%
Strosznajder R. P., Jesko H., Adamczyk A.
Journal of Physiology and Pharmacology. Supplement
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2005
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tom 56
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nr 4
209-213
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and transcription regulation. The aim of this study was to investigate the role of PARP-1 in muscarinic cholinergic receptor signaling. Our data indicate that activation of muscarinic cholinergic receptors by carbachol (1mM) in the presence of GTPS evoked a significant enhancement of PARP activity in the adult rat hippocampus. Moreover, TMB-8 (10µM), an antagonist of inositol 1, 4, 5 trisphosphate (IP3) receptor prevented the activation of PARP-1, which indicates that IP3 /Ca2+ signaling is involved in this pathway. The diacylglycerol (DAG)-regulated protein kinase C (PKC) inhibitor (GF109203X) (1µM) only slightly enhanced PARP activity in hippocampal nuclear fractions, which suggests that DAG/ PKC is not involved in PARP activation.
6
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Effects of p53 inhibitor on survival and death of cells subjected to oxidative stress

100%
Strosznajder R. P., Jesko H., Banasik M., Tanaka S.
Journal of Physiology and Pharmacology. Supplement
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2005
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tom 56
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nr 4
215-221
Our previous data indicate that ischemia and amyloid beta peptide (Abeta) cause an oxidative damage to macromolecules. In the present study we investigated the role of p53 protein in cell survival and death after administration of Abeta. The experiments were carried out on pheochromocytoma cells (PC-12) and cortical primary neurons in culture. The cortical neurons were exposed (48 h, 10 µM) to the action of a short Abeta25-35 neurotoxic fragment and the involvement of p53 was evaluated after addition of the p53 inhibitor pifithrin-alpha. Changes in cell morphology were evaluated by 4', 6-diamidino-2-phenylindole staining and the concentration-dependent effect of pifithrin-alpha on cells viability was determined. Additionally, we studied the effect of pifithrin-alpha on neuronal survival in vivo after a 5-min global brain ischemia followed by 7 days' reperfusion in gerbils. We found that Abeta enhanced apoptotic cell death in cortical primary neurons. Pifithrin-alpha, at a 10 µM final concentration, protected the neuronal cells from the apoptotic death. However, at concentrations of 0.1 and 1 mM, the p53 inhibitor decreased PC-12 cells' viability in a dose-dependent manner. In in vivo experiments we did not observe any neuroprotection by pifithrin-alpha in the CA1 hippocampal layer, which suggests that its effects strongly depend on the duration and type of an ischemic insult. Our data indicate that pifithrin-alpha affects neuronal cells in a dual manner. It has a protective effect at a low concentration, but becomes neurotoxic at higher concentrations.
7

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

100%
Cakala M., Jesko H., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
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2006
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tom 66
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nr 4
8

Fingolimod (FTY720 - modulator of sphingosine 1-phosphate receptors) alters genes expression of selected NADplus-dependent enzymes in an animal model of Alzheimer’s disease

100%
Wencel P., Jesko H., Strosznajder R. P.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) belong to the family of NAD+ ‑dependent enzymes. Both are involved in the regulation of energy homeostasis, cellular stress response, and DNA repair. Recent data suggest that alterations of bioactive sphingolipids level as well as SIRTs and PARPs may be involved in Alzheimer’s disease (AD) pathology, finally leading to the progression of disease. AIM(S): In this study, the effect of FTY720 administration on mRNA levels of SIRTs and PARP‑1 in an animal model of AD was examined. METHOD(S): 3‑, 6‑, and 12‑month‑old (3M, 6M, 12M) FVB/APP+ transgenic mice with London APP (V717I) mutation were used in this study. Mice without the mutation (APP- ) were used as the control. Animals received i.p. FTY720 (1mg/kg b.w.) or NaCl (vehicle) for 2 weeks. Brain cortex was isolated and qPCR methods were applied. RESULTS: A significant downregulation of Sirt1 mRNA levels in the cortex of 3M APP+ mice vs. APP- was observed. We also observed a tendency for a reduction of 6M Sirt3 and Sirt4 mRNA levels in APP+ mice. Administration of FTY720 increased mRNA levels of Sirt1 in 3M APP+ mice as well as Parp1, Sirt1, 3, 5 in 6M APP+ mice compared to APP+ mice treated with vehicle. Moreover, FTY720 elevated Parp1, Sirt1, and Sirt3 mRNA levels in 12M APP+ mice. CONCLUSIONS: The results of our study revealed a potential link between bioactive sphingolipids and NAD+ ‑dependent enzymes. These results may also indicate an FTY720-modulatory role in SIRTs and PARPs gene expression and may offer a useful tool in the therapeutic strategy of neurodegenerative disorders. FTY720, through the activation of mitochondrial sirtuins (Sirt3,5), may improve anti-oxidative defense and protect cells against oxidative stress evoked by amyloid beta toxicity. Moreover, through activation of Sirt1 and Parp1 gene expression, FTY720 may enhance DNA repair processes. FINANCIAL SUPPORT: Supported by the National Science Centre grant no. NCN 2014/15/B/NZ3/01049 and Mossakowski MRC PAS statutory theme no.7.
9

Amyloid beta peptides evoke alteration of cholinergic phosphoinositide signals, lipid peroxidation and PARP activity in brain

100%
Zambrzycka A., Jesko H., Strosznajder R. P., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
1999
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tom 59
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nr 3
10

Age-related alteration of poly[ADP-ribose] polymerase activity in different parts of the brain

100%
Strosznajder J. B., Jesko H., Strosznajder R. P.
Acta Biochimica Polonica
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2000
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tom 47
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nr 2
Poly(ADP-ribose) polymerase (PARP) is a conserved enzyme involved in the regulation of DNA repair and genome stability. The role of PARP during aging is not well known. In this study PARP activity was investigated in nuclear fractions from hippocampus, cerebellum, and cerebral cortex of adult (4 months), old adult (14 months) and aged (24-27 months) rats. Concomitantly, the free radical evoked lipid peroxidation was estimated as thiobarbituric acid reactive substances (TBARS). The specific activity of PARP in adult brain was about 25, 21 and 16 pmol/mg protein per min in hippocampus, cerebellum and cerebral cortex, respectively. The enzyme activity was higher in all investigated parts of the brain of old adults. In aged animals PARP activity was lower in hippocampus by about 50%, and was unchanged in cerebral cortex and in cerebellum comparing to adult rats. The concentration of TBARS was the same in all parts of the brain and remained unchanged during aging. There is no direct correlation between PARP activity and free radical evoked lipid peroxidation during brain aging. The lowered enzyme activity in aged hippocampus may decrease DNA repair capacity which subsequently may be responsible for the higher vulnerability of hippocampal neurons to different toxic insults.
11

Effect of carvedilol on neuronal survival and poly[ADP-ribose] polymerase activity in hippocampus after transient forebrain ischemia

100%
Strosznajder R. P., Jesko H., Dziewulska J.
Acta Neurobiologiae Experimentalis
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2005
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tom 65
|
nr 2
12

Effect of aging and oxidative-genotoxic stress on poly[ADP-ribose] polymerase-1 activity in rat brain

100%
Strosznajder R. P., Jesko H., Adamczyk A.
Acta Biochimica Polonica
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2005
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tom 52
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nr 4
Poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30), a DNA-bound enzyme, plays a key role in genome stability, but after overactivation can also be responsible for cell death. The aim of the present study was to investigate PARP-1 activity in the hippocampus, brain cortex, striatum and cerebellum in adult (4 months) and aged (24 months) specific pathogen free Wistar rats and to correlate it with PARP-1 protein level and p53 expression. Moreover, the response of PARP-1 in adult and aged hippocampus to oxidative/genotoxic stress was evaluated. Our data indicated a statistically significant enhancement of PARP-1 activity in aged hippocampus and cerebral cortex comparing to adults without statistically significant changes in PARP-1 protein level. The expression of p53 mRNA was elevated in all aged brain parts with the exception of the cerebral cortex. Our data suggest that enhancement of PARP-1 activity and p53 expression in aged brain may indicate higher DNA damage. Our data also indicate that during excessive oxidative/genotoxic stress there is no response of PARP-1 activity in aged hippocampus in contrast to a significant enhancement of PARP-1 activity in adults which may have important consequences for the physiology and pathology of the brain.
13

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

100%
Strosznajder J. B., Jesko H., Strosznajder R. P.
Acta Biochimica Polonica
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2000
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tom 47
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nr 3
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.
14
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Poly(ADP-ribose) polymerase activity in the cat carotid body in hypoxia and hyperoxia

100%
Strosznajder R. P., Jesko H., Pokorski M.
Journal of Physiology and Pharmacology
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2002
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tom 53
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nr 3
Reactive oxygen species (ROS) induce DNA damage with the ensuing activation of the chromosomal repair enzyme poly(ADP-ribose) polymerase (PARP). ROS also interact with the function of carotid body chemoreceptor cells. The possibility arises that PARP is part of the carotid chemosensing process. This study seeks to determine the presence of PARP and its changes in response to contrasting chemical stimuli, hypoxia and hyperoxia, both capable of generating ROS, in cat carotid bodies. The organs were dissected from anesthetized cats exposed in vivo to acute normoxic (PaO290 mmHg), hypoxic (PaO225 mmHg), and hyperoxic (PaO2> 400 mmHg) conditions. Carotid body homogenate was the source of PARP and [adenine 14C] NAD was the substrate in the assay. Specimens of the superior cervical ganglion and brainstem were used as reference tissues. We found that PARP activity amounted to 27 pmol/mg protein/min in the normoxic carotid body. The activity level more than doubled in both hypoxic and hyperoxic carotid bodies. Changes of PARP in the reference tissues were qualitatively similar. We conclude that PARP is present in the carotid body but the augmentation of the enzyme activity in both hypoxia and hyperoxia reflects DNA damage, induced likely by ROS and being universal for neural tissues, rather than a specific involvement of PARP in the chemosensing process.
15

Nitric oxide and poly(ADP- ribose) polymerase in signal transduction and neurodegeneration

88%
Strosznajder J., Jesko H., Chalimoniuk M., Zambrzycka A., Strosznajder R.
Acta Biochimica Polonica
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2003
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tom 50
|
nr Supplement 1
16

Molecular mechanism of PC12 cell death evoked by sodium nitroprusside, a nitric oxide donor

88%
Pytlowany M., Strosznajder J. B., Jesko H., Cakala M., Strosznajder R. P.
Acta Biochimica Polonica
|
2008
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tom 55
|
nr 2
339-347
Nitric oxide (NO) is a potent extracellular and intracellular physiological messenger. However, NO liberated in excessive amounts can be involved in macromolecular and mitochondrial damage in brain aging and in neurodegenerative disorders. The molecular mechanism of its neurotoxic action is not fully understood. Our previous data indicated involvement of NO in the release of arachidonic acid (AA), a substrate for cyclo- and lipoxygenases (COX and LOX, respectively). In this study we investigated biochemical processes leading to cell death evoked by an NO donor, sodium nitroprusside (SNP). We found that SNP decreased viability of pheochromocytoma (PC12) cells in a concentration- and time-dependent manner. SNP at 0.1 mM caused a significant increase of apoptosis-inducing factor (AIF) protein level in mitochondria. Under these conditions 80% of PC12 cells survived. The enhancement of mitochondrial AIF level might protect most of PC12 cells against death. However, NO released from 0.5 mM SNP induced massive cell death but had no effect on protein level and localization of AIF and cytochrome c. Caspase-3 activity and poly(ADP-ribose) polymerase-1 (PARP-1) protein levels were not changed. However, PARP activity significantly decreased in a time-dependent manner. Inhibition of both COX isoforms and of 12/15-LOX significantly lowered the SNP-evoked cell death. We conclude that AIF, cytochrome cand caspase-3 are not responsible for the NO-mediated cell death evoked by SNP. The data demonstrate that NO liberated in excess decreases PARP-1 activity. Our results indicate that COX(s) and LOX(s) are involved in PC12 cell death evoked by NO released from its donor, SNP.
17

Mitochondrial and nuclear targets of amyloid wita-evoked oxidative stress

88%
Jesko H., Strosznajder J., Cieslik M., Cakala M., Strosznajder R.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
Amyloid β (Aβ) is responsible for mitochondrial failure and biochemical alterations linked to Alzheimer`s disease (AD). To better understand mechanisms of Aβ toxicity we investigated its mitochondrial and nuclear targets, apoptosis-inducing factor (AIF) and Poly(ADP-ribose) polymerase-1 (PARP-1) in PC12 cells transfected with wild type (APPwt) or double Swedish-mutated human Amyloid Precursor Protein gene (APPsw) characterized by different Aβ concentrations. We found close relationship between Aβ level and cyclooxygenase (COX)- and lipoxygenase (LOX)-related free radical formation leading to p65/NF-κB nuclear translocation. COX and LOX inhibitors protected APPsw cells against p65 translocation. Aβ-evoked oxidative stress enhanced mitochondrial AIF level and inhibited PARP-1 in APPsw cells. Nitrosative stress evoked by 0.5 mM sodium nitroprusside (SNP) had no further effect on Aβ-altered PARP-1 activity and mitochondrial AIF level in APPsw cells. However, SNP evoked death of 70–80% of all cell types after 24 h. COX and LOX inhibitors had ameliorating effect in these conditions. Our data indicated that double Swedish mutation in APP signifi cantly increased cell vulnerability to oxidative stress. Enhanced mitochondrial AIF level and PARP-1 inhibition might be responsible for cell survival under oxidative stress evoked by accumulating Aβ in APPsw cells. COX and LOX inhibitors protected the cells against death caused by simultaneous Aβ toxicity and nitrosative stress.
18

Alteration of mTOR signalling pathway in rats prenatally exposed to valproic acid

76%
Adamczyk A., Cieslik M., Gassowska-Dobrowolska M., Jesko H., Filipkowski R. K., Boguszewski P. M.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Autism is a neurodevelopmental disorder characterised by impaired social interaction, deficits in communication and stereotyped behaviours with synaptic dysfunction suggested as the major causative factor. However, the molecular mechanisms of synapses impairment remain unclear. The most recent studies point to mTOR, a regulator of protein synthesis at spines, as a potential molecular basis of autism. AIM(S): Here, we investigated whether the Akt/mTOR pathway is damaged in rats prenatally exposed to valproic acid (VPA), an animal model exhibiting autistic-like behaviour. METHOD(S): Pregnant Wistar rats were injected i.p. with a single dose of 400 mg/kg VPA on embryonic day 12.5. Autism‑like behaviours were verified by measuring ultrasonic vocalizations and elevated plus maze test. Gene expression and protein levels were analysed using real-time PCR and western blot methods, respectively. RESULTS: Our behavioural investigations have shown impaired communication and increased anxiety in VPA group. Along with the behavioural changes we observed alteration of mTOR signalling in the cerebral cortex, hippocampus and cerebellum of autistic model rats. Enhancement of phospho-mTOR protein level was the most pronounced in the hippocampus, where the phosphorylation of mTOR targets was observed: increased p-4E-BP1, and reduced phospho-p70S6K. These changes were accompanied by an increase in p-Akt protein level. Activation of mTOR in the cerebellum caused an increase of p-4E-BP1, but not of p70S6K. The mild but significant rise in phosphorylated mTOR in the cerebral cortex did not lead to any changes in p70 or 4E-BP1 phosphorylation. Synaptosomes isolated from VPA subjects revealed significant abnormalities in their ultrastructure including unidentified electron-dense matrix material as well as fragile and malformed the post-synaptic densities. CONCLUSIONS: These results suggested that altered signalling via Akt/mTOR/p70S6K/p-4E-BP1 may result in disturbed spine protein synthesis and thereby lead to synaptic dysfunction. FINANCIAL SUPPORT: Supported from MMRC statutory theme 8.
19

Maternal immune activation dysregulates the synaptic ProSAP/Shank expression and might contribute to autism spectrum disorders

76%
Adamczyk A., Cieslik M., Jesko H., Jaron K., Dominiak A., Smietanka U., Boguszewski P. M.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Autism spectrum disorders (ASD) are neurodevelopmental diseases impairing social behaviour and cognition. Shank proteins that are involved in the maturation and maintenance of synaptic function have been implicated in the pathogenesis of ASD. Prenatal maternal immune activation (MIA) is a risk factor for ASD and is commonly used as animal model of ASD. METHODS: We investigated the effect of MIA on the expression of Shank1, 2, 3 in male offspring of Wistar rats ip injected with 0.1 mg/kg lipopolysaccharide at gestational day 9.5. Moreover, redox potential and pro-oxidative/pro-inflammatory proteins were analysed along with the autism-associated behaviour. Gene expression and protein levels were analysed using Real-time PCR and Western blot methods, respectively. Glutathione was measured spectrophotometrically. Behavioural tests were conducted to assess social communication, motions and anxiety, play behaviours as well as learning and memory. RESULTS: The data showed MIA-induced down-regulation of Shank1, 2 and 3 in the cerebral cortex, without changes in other brain structures. The GSH/GSSG ratio has been used as an indicator of oxidative stress. MIAslightly decreased the reduced GSH level butsignificantly elevated the GSSG level, which led to reduction of the GSH/GSSG ratio in brain cortex. Furthermore, we analysed the expression of cyclooxygenase-2 (COX-2) as well as 12-lipoxygenase (LOX-12) that may be engaged in oxidative stress depending on cellular redox state and found up-regulation of both COX-2 and LOX-12 in the cerebral cortex. Along with the biochemical changes MIAevoked a tendency towards impaired pup communication (ultrasonic vocalization) and learning and memory (Tmaze) in adult animals. CONCLUSIONS: Our findingsindicate MIA-induced down-regulation of Shank family and reduced antioxidative capacity. These changes may disturb synaptic function and social/cognitive behaviour. Supported from MMRC statutory theme 8.
20

Maternal immune activation alters synaptic protein expression and causes social interaction impairment in rat offspring

76%
Cieslik M., Gassowska-Dobrowolska M., Jesko H., Boguszewski P. M., Filipkowski R. K., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2017
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tom 77
|
nr Suppl.1
INTRODUCTION: Emerging epidemiology data indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as bacterial infections during pregnancy may constitute a risk factor for multiple neurodevelopmental diseases including autism spectrum disorders (ASD). Genetic and environmental variation, inflammation during early development, and their interaction can influence synaptic dysfunction in ASD. However, the molecular links between infection-induced fetal development alterations and the risk of ASD are still unclear. AIM(S): The aim of this study was to investigate the effect of MIA on the expression and protein level of key synaptic proteins along with the autism-associated behavior in male rat offspring. METHOD(S): Pregnant Wistar rat dams were injected intraperitoneally (i.p.) at gestational day 9.5 with 0.1 mg/kg lipopolysaccharide (LPS), which induces immune response similar to that against gram-negative bacteria. RESULTS: Our data shown impaired social interaction, tested by the play behaviors (Tickling test on post-natal day PND 45–50). However, we did not observe any changes in ultrasonic vocalization (9–11 PND) and bedding preference (PND 15) in MIA offspring. Along with the social interaction changes, MIA has induced presynaptic protein alterations in adolescent rat offspring. These alterations included decreased level of synaptobrevin and syntaxin-1, the key components of SNARE complex, as well as higher level of synapsin. Together with changes in presynaptic proteins, MIA induced reduction in PSD-95 and down-regulation of SHANK family proteins. Moreover, alteration in the protein level of phospho-Akt, and 4E-BP1 was found in MIA subjects. CONCLUSIONS: It is possible that variations of Akt/ mTOR pathway are responsible for aberrant synthesis of key synaptic proteins. The altered synthesis of these proteins would generate changes in synaptic structure and function, contributing to ASD-like behaviors. FINANCIAL SUPPORT: Supported by the statutory theme 8.
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