Wybrane publikacje

Mechanisms of Excessive Extracellular Glutamate Accumulation in Temporal Lobe Epilepsy.

Neurochem Res. 2017 Jun;42(6):1724-1734. doi: 10.1007/s11064-016-2105-8. Epub 2016 Nov 21.

Albrecht J1, Zielińska M2.

Mechanisms of Excessive Extracellular Glutamate Accumulation in Temporal Lobe Epilepsy.

Author information

1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2     Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.

ABSTRACT:

There is compelling evidence that initiation and maintenance of epileptic seizures in temporal lobe epilepsy (TLE) is facilitated by excessive accumulation in the extracellular (perisynaptic) space of the excitatory neurotransmitter glutamate (Glu). This review discusses the mechanisms underlying this phenomenon. Glu released from neurons is taken up by astrocytes and activated there by glutamine synthetase (GS) to form glutamine (Gln) which upon entry to neurons is degraded back to Glu by phosphate-activated glutaminase (PAG): this chain of reactions has been defined as the glutamine/glutamate/cycle (GGC). In the initial phase of epileptogenesis, increased Glu supply is a consequence of activation of its turnover in GGC by Glu released by a primary chemical or physical stimulus. In chronic TLE, profound astrogliosis and demise of neurons which culminate in hippocampal sclerosis, are associated with changes in GGC which act in concert towards increasing the extracellular Glu concentration. Deficiency of GS and of the astrocytic Glu transporter, GLT-1, impede Glu inactivation, whereas Glu release from neurons appears facilitated by activation of PAG and increased activity of the neuronal Glu transporter EAAC1. Conclusions derived from measurements of activities/expression patterns of the GGC enzymes and transporter moieties find support in metabolic studies employing 13C labeled Glu precursors. Glu reuptake by astrocytes is additionally impeded by unfavorable ion gradients resulting from ion and water dyshomeostasis, and extracellular Glu concentration is further increased by reduction of extracellular space due to edema and altered cytoarchitecture of the hippocampus. Missing links in the scenario are discussed in concluding comments.

KEYWORDS:

Astrocytes; Extracellular glutamate; Glutamine glutamate cycle; Neurons; Temporal lobe epilepsy

MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer.

Stem Cell Reports. 2017 Jun 6;8(6):1497-1505. doi: 10.1016/j.stemcr.2017.04.024. Epub 2017 May 18.
Godlewski J1, Ferrer-Luna R2, Rooj AK3, Mineo M3, Ricklefs F4, Takeda YS3, Nowicki MO3, Salińska E5, Nakano I6, Lee H7, Weissleder R8, Beroukhim R2, Chiocca EA3, Bronisz A9.
MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer.
Author information
1   Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
2    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Cancer Program, BROAD Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5  Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences 02-106 Warsaw, Poland.
6  Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35243, USA.
7 Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
8   Department of Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
9    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:
Despite the importance of molecular subtype classification of glioblastoma (GBM), the extent of extracellular vesicle (EV)-driven molecular and phenotypic reprogramming remains poorly understood. To reveal complex subpopulation dynamics within the heterogeneous intratumoral ecosystem, we characterized microRNA expression and secretion in phenotypically diverse subpopulations of patient-derived GBM stem-like cells (GSCs). As EVs and microRNAs convey information that rearranges the molecular landscape in a cell type-specific manner, we argue that intratumoral exchange of microRNA augments the heterogeneity of GSC that is reflected in highly heterogeneous profile of microRNA expression in GBM subtypes.
Published by Elsevier Inc.
KEYWORDS:
GBM; cancer heterogeneity; cancer stem cells; exosomes; extracellular vesicles; glioblastoma; microRNA; subtypes

Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1).

Russell-Jones D1, Bode BW2, De Block C3, Franek E4, Heller SR5, Mathieu C6, Philis-Tsimikas A7, Rose L8, Woo VC9, Østerskov AB10, Graungaard T10, Bergenstal RM11.

Diabetes Care. 2017 Jul;40(7):943-950. doi: 10.2337/dc16-1771. Epub 2017 Mar 29.

Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1).

 1   Diabetes and Endocrinology, Royal Surrey County Hospital, and University of Surrey, Guildford, U.K. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2 Atlanta Diabetes Associates, Atlanta, GA.

3  Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, Antwerp, Belgium.

4  Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.

5    Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.

6    Clinical and Experimental Endocrinology, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium.

7    Scripps Whittier Diabetes Institute, Scripps Health, San Diego, CA.

8    Institute of Diabetes Research, Münster, Germany.

9    Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada.

10     Novo Nordisk A/S, Søborg, Denmark.

11     International Diabetes Center at Park Nicollet, Minneapolis, MN.

 

ABSTRACT:

OBJECTIVE:

This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS:

The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)-each with insulin detemir.

RESULTS:

HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart-IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI -1.65; -0.71], -21.21 mg/dL [-29.65; -12.77]; P < 0.0001) and 2 h (-0.67 mmol/L [-1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments.

 

CONCLUSIONS:

Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Popek M1, Bobula B2, Sowa J2, Hess G2, Polowy R3, Filipkowski RK3, Frontczak-Baniewicz M4, Zabłocka B5, Albrecht J1, Zielińska M6.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Author information:

1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

2 Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.

3 Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

4 Electron Microscopy Platform, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

5 Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

6 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

 

ABSTRACT:

Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18-1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.

KEYWORDS:

Acute liver failure; Neurotransmission; Presynaptic events

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin.

Exp Neurol. 2017 May;291:74-86. doi: 10.1016/j.expneurol.2017.02.005. Epub 2017 Feb 2.

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin.

Lyczek A1, Arnold A1, Zhang J2, Campanelli JT3, Janowski M4, Bulte JW1, Walczak P5.

Author information:

1 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States.

2 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States.

3 Q Therapeutics, Inc., Salt Lake City, UT 84108, United States.

4 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurosurgery, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland; Dept. of NeuroRepair, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland.

5 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:

The therapeutic effect of glial progenitor transplantation in diseases of dysmyelination is currently attributed to the formation of new myelin. Using magnetic resonance imaging (MRI), we show that the therapeutic outcome in dysmyelinated shiverer mice is dependent on the extent of cell migration but not the presence of mature and compact myelin. Human or mouse glial restricted progenitors (GRPs) were transplanted into rag2-/- shiverer mouse neonates and followed for over one year. Mouse GRPs produced mature myelin as detected with multi-parametric MRI, but showed limited migration without extended animal lifespan. In sharp contrast, human GRPs migrated extensively and significantly increased animal survival, but production of mature myelin did not occur until 46weeks post-grafting. We conclude that human GRPs can extend the survival of transplanted shiverer mice prior to production of mature myelin, while mouse GRPs fail to extend animal survival despite the early presence of mature myelin. This paradox suggests that transplanted GRPs provide therapeutic benefits through biological processes other than the formation of mature myelin capable to foster rapid nerve conduction, challenging the current dogma of the primary role of myelination in regaining function of the central nervous system.

KEYWORDS:

Glial progenitors; MRI; Myelin; Shiverer; Transplantation

Ischemia/Reperfusion-Induced Translocation of PKCβII to Mitochondria as an Important Mediator of a Protective Signaling Mechanism in an Ischemia-Resistant Region of the Hippocampus

Krupska O1, Sarnowska A2, Fedorczyk B3, Gewartowska M4, Misicka A3,5, Zablocka B1, Beresewicz M6.

 

Ischemia/Reperfusion-Induced Translocation of PKCβII to Mitochondria as an Important Mediator of a Protective Signaling Mechanism in an Ischemia-Resistant Region of the Hippocampus.

 

1 Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

2 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

3 Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

4 Electron Microscopy Platform, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

5 Department of Neuropeptides, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

6 Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:

Emerging reports indicate that activated PKC isoforms that translocate to the mitochondria are pro- or anti-apoptotic to mitochondrial function. Here, we concentrate on the role of PKCβ translocated to mitochondria in relation to the fate of neurons following cerebral ischemia. As we have demonstrated previously ischemia/reperfusion injury (I/R) results in translocation of PKCβ from cytoplasm to mitochondria, but only in ischemia-resistant regions of the hippocampus (CA2-4, DG), we hypothesize that this translocation may be a mediator of a protective signaling mechanism in this region. We have therefore sought to demonstrate a possible relationship between PKCβII translocation and ischemic resistance of CA2-4, DG. Here, we reveal that I/R injury induces a marked elevation of PKCβII protein levels, and consequent enzymatic activity, in CA2-4, DG in the mitochondrial fraction. Moreover, the administration of an isozyme-selective PKCβII inhibitor showed inhibition of I/R-induced translocation of PKCβII to the mitochondria and an increase in neuronal death following I/R injury in CA1 and CA2-4, DG in both an in vivo and an in vitro model of ischemia. The present results suggest that PKCβII translocated to mitochondria is involved in providing ischemic resistance of CA2-4, DG. However, the exact mechanisms by which PKCβII-mediated neuroprotection is achieved are in need of further elucidation.

KEYWORDS:

Cerebral ischemia; Endogenous neuroprotection; Mitochondria; PKCβII; Protein kinase C

Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

Gąssowska M1, Baranowska-Bosiacka I2, Moczydłowska J3, Frontczak-Baniewicz M4, Gewartowska M4, Strużyńska L5, Gutowska I6, Chlubek D7, Adamczyk A8.

Toxicology. 2016 Dec 12;373:13-29. doi: 10.1016/j.tox.2016.10.014. Epub 2016 Oct 29.

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Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system.

Walczak P1, Wojtkiewicz J2, Nowakowski A3, Habich A2, Holak P4, Xu J5, Adamiak Z4, Chehade M6, Pearl MS7, Gailloud P7, Lukomska B3, Maksymowicz W8, Bulte JW9, Janowski M10.

J Cereb Blood Flow Metab. 2016 Sep 12. pii: 0271678X16665853. [Epub ahead of print]

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Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.

Liu H1, Jablonska A2, Li Y3, Cao S4, Liu D5, Chen H5, Van Zijl PC3, Bulte JW3, Janowski M6, Walczak P2, Liu G3.

 Theranostics. 2016 Jun 18;6(10):1588-600. doi: 10.7150/thno.15492. eCollection 2016.

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Altered arginine metabolism in cells transfected with human wild-type beta amyloid precursor protein (βAPP).

Jęśko H, Wilkaniec A, Cieślik M, Hilgier W, Gąssowska M, Lukiw WJ, Adamczyk A

Altered arginine metabolism in cells transfected with human wild-type beta amyloid precursor protein (βAPP).

Department of Cellular Signalling, Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

Curr Alzheimer Res. 2016 Mar 14. [Epub ahead of print]

 

Abstract

 

Alterations of enzymes linked to arginine metabolism have been recently implicated in Alzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO) pathway, the impact of amyloid β (Aβ) peptides on arginine degradation and re-synthesis is unknown. In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelial and inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesize it from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressing human Aβ precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible for modulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases of ARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantly lower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable in both cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated without changes in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescine was also reduced. Arginine, the substrate for both arginases and NOS, was unchanged in APPwt cells. However, citrulline concentration was significantly higher. Elevated miRNA-9 and miRNA-128a found in AD brain tissues might modulate the expression of ASS and NOS, respectively. Our results indicate that Aβ affects arginine metabolism and this influence might have important role in the pathomechanism of AD.

 

PMID:26971935 [PubMed - as supplied by publisher]

 

Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

Gąssowska Ma, Baranowska-Bosiacka Ib, Moczydłowska Ja, Tarnowski Mc, Pilutin Ad, Gutowska Ie, Strużyńska Lf, Chlubek Db, Adamczyk Aa

Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

a Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw

b Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin

c Department of Physiology, Pomeranian Medical University, Szczecin

d Department of Histology and Embryology, Pomeranian Medical University, Szczecin

e Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Szczecin

f Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw

 

Toxicology. 2016 Mar 10;347-349:17-28. doi: 10.1016/j.tox.2016.03.002. Epub 2016 Mar 21.

 

Abstract

 

Hyperphosphorylation of Tau is involved in the pathomechanism of neurological disorders such as Alzheimer's, Parkinson's diseases as well as Autism. 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. The purpose of this study was to evaluate the effect of perinatal exposure to low dose of Pb on the Tau pathology in the developing rat brain. 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 evaluated. Pregnant female rats were divided into control and Pb-treated group. The control animals were maintained on drinking water while females from the Pb-treated group received 0.1% lead acetate (PbAc) in drinking water, starting from the first day of gestation until weaning of the offspring. During the feeding of pups, mothers from the Pb-treated group were still receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and Tau mRNA and protein level as well as Tau phosphorylation were analyzed in forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the effect of Pb exposure on GSK-3β and CDK5 activation. Our data revealed that pre- and neonatal exposure to Pb (concentration of Pb in whole blood below 10μg/dL, considered safe for humans) caused significant increase in the phosphorylation of Tau at Ser396 and Ser199/202 with parallel rise in the level of total Tau protein in FC and C. Tau hyperphosphorylation in Pb-treated animals was accompanied by elevated activity of GSK-3β and CDK5. Western blot analysis revealed activation of GSK-3β in FC and C as well as CDK5 in C, via increased phosphorylation of Tyr-216 and calpain-dependent p25 formation, respectively. In conclusion, perinatal exposure to Pb up-regulates Tau protein level and induces Tau hyperphosphorylation in the rat brain cortex and cerebellum. We suggest that neurotoxic effect of Pb might be mediated, at least in part, by GSK-3β and CDK5-dependent Tau hyperphosphorylation, which may lead to the impairment of cytoskeleton stability and neuronal dysfunction.

 

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

 

KEYWORDS: CDK5; GSK-3β; Hyperphosphorylation; Lead neurotoxicity; Rat brain; Tau protein

 

The mechanisms regulating cyclin-dependent kinase 5 in hippocampus during systemic inflammatory response: The effect on inflammatory gene expression.

Czapski GA1, Gąssowska M2, Wilkaniec A2, Chalimoniuk M2, Strosznajder JB2, Adamczyk A2.

The mechanisms regulating cyclin-dependent kinase 5 in hippocampus during systemic inflammatory response: The effect on inflammatory gene expression.

1Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, ul. Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, ul. Pawińskiego 5, 02-106 Warsaw, Poland.

Neurochem Int. 2016 Feb;93:103-12. doi: 10.1016/j.neuint.2016.01.005. Epub 2016 Jan 21.

Abstract

Cyclin-dependent kinase 5 (Cdk5) is critical for nervous system's development and function, and its aberrant activation contributes to pathomechanism of Alzheimer's disease and other neurodegenerative disorders. It was recently suggested that Cdk5 may participate in regulation of inflammatory signalling. The aim of this study was to analyse the mechanisms involved in regulating Cdk5 activity in the brain during systemic inflammatory response (SIR) as well as the involvement of Cdk5 in controlling the expression of inflammatory genes. Genetic and biochemical alterations in hippocampus were analysed 3 and 12 h after intraperitoneal injection of lipopolysaccharide. We observed an increase in both Cdk5 gene expression and protein level. Moreover, phosphorylation of Cdk5 on Ser159 was significantly enhanced. Also transcription of Cdk5-regulatory protein (p35/Cdk5r1) was augmented, and the level of p25, calpain-dependent cleavage product of p35, was increased. All these results demonstrated rapid activation of Cdk5 in the brain during SIR. Hyperactivity of Cdk5 contributed to enhanced phosphorylation of tau and glycogen synthase kinase 3β. Inhibition of Cdk5 with Roscovitine reduced activation of NF-κB and expression of inflammation-related genes, demonstrating the critical role of Cdk5 in regulation of gene transcription during SIR.

Copyright © 2016 Elsevier Ltd. All rights reserved.

KEYWORDS: Cyclin-dependent kinase 5; Hippocampus; Lipopolysaccharide; Neuroinflammation; Systemic inflammation

 

Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Pająk B1,2, Kania E1, Orzechowski A1,2  

Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Oxid Med Cell Longev. 2016;2016:1805304. doi: 10.1155/2016/1805304. Epub 2016 Jan 6.

1Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland;

2Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.

 

Abstract

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.

 

PMID: 26881014 [PubMed - in process]  PMCID: PMC4736771

Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status.

Szeliga M, Bogacińska-Karaś M, Kuźmicz K, Rola R, Albrecht J.

Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status.

Mol Carcinog. 2015 Aug 10. doi: 10.1002/mc.22372.

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Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism.

Grieb P.

Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism.

Mol Neurobiol. 2015 Mar 7.

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Sphingosine-1-phosphate and its effect on glucose deprivation/glucose reload stress: from gene expression to neuronal survival.

Czubowicz K1, Cieślik M, Pyszko J, Strosznajder JB, Strosznajder RP.

Sphingosine-1-phosphate and its effect on glucose deprivation/glucose reload stress: from gene expression to neuronal survival.

Mol Neurobiol. 2015 Jun;51(3):1300-8. doi: 10.1007/s12035-014-8807-5. Epub 2014 Jul 24.

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Pre- and postmortem imaging of transplanted cells

Anna Andrzejewska, Adam Nowakowski, Miroslaw Janowski, Jeff WM Bulte, Assaf A Gilad, Piotr Walczak, and Barbara Lukomska

Pre- and postmortem imaging of transplanted cells

Int J Nanomedicine. 2015; 10: 5543–5559.

Published online 2015 Sep 2. doi:  10.2147/IJN.S83557

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The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins.

Cieślik M, Czapski GA, Strosznajder JB.

The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins.

PLoS One. 2015 Sep 3;10(9):e0137193. doi: 10.1371/journal.pone.0137193. eCollection 2015.

Cieślik M, Czapski GA, Strosznajder JB.

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Role of atrial natriuretic peptide in mediating...

Dobrowolski L, Kuczeriszka M, Castillo A, Majid DS, Navar LG.

"Role of atrial natriuretic peptide in mediating the bloodpressure-independent natriuresis elicited by systemic inhibition of nitricoxide."

Pflugers Arch. 2014 Jun 24.

Leszek Dobrowolski, Marta Kuczeriszka - Department of Renal and Body Fluid Physiology, MMRC

Abstract