Selected publications

Directed glial differentiation and transdifferentiation for neural tissue regeneration.

Exp Neurol. 2019 Sep;319:112813. doi: 10.1016/j.expneurol.2018.08.010. Epub 2018 Aug 30.

Janowska J1, Gargas J1, Ziemka-Nalecz M1, Zalewska T1, Buzanska L2, Sypecka J3.

Author information

1 Mossakowski Medical Research Centre, Polish Academy of Sciences, NeuroRepair Department, 5, Pawinskiego str., 02-106 Warsaw, Poland.

2 Mossakowski Medical Research Centre, Polish Academy of Sciences, Stem Cell Bioengineering Unit, 5, Pawinskiego str., 02-106 Warsaw, Poland.

3 Mossakowski Medical Research Centre, Polish Academy of Sciences, NeuroRepair Department, 5, Pawinskiego str., 02-106 Warsaw, Poland. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Glial cells which are indispensable for the central nervous system development and functioning, are proven to be vulnerable to a harmful influence of pathological cues and tissue misbalance. However, they are also highly sensitive to both in vitro and in vivo modulation of their commitment, differentiation, activity and even the fate-switch by different types of bioactive molecules. Since glial cells (comprising macroglia and microglia) are an abundant and heterogeneous population of neural cells, which are almost uniformly distributed in the brain and the spinal cord parenchyma, they all create a natural endogenous reservoir of cells for potential neurogenerative processes required to be initiated in response to pathophysiological cues present in the local tissue microenvironment. The past decade of intensive investigation on a spontaneous and enforced conversion of glial fate into either alternative glial (for instance from oligodendrocytes to astrocytes) or neuronal phenotypes, has considerably extended our appreciation of glial involvement in restoring the nervous tissue cytoarchitecture and its proper functions. The most effective modulators of reprogramming processes have been identified and tested in a series of pre-clinical experiments. A list of bioactive compounds which are potent in guiding in vivo cell fate conversion and driving cell differentiation includes a selection of transcription factors, microRNAs, small molecules, exosomes, morphogens and trophic factors, which are helpful in boosting the enforced neuro-or gliogenesis and promoting the subsequent cell maturation into desired phenotypes. Herein, an issue of their utility for a directed glial differentiation and transdifferentiation is discussed in the context of elaborating future therapeutic options aimed at restoring the diseased nervous tissue.

KEYWORDS:

Cell fate conversion; Glial cell reprogramming; Neural development transdifferentiation; Neurorepair; Pre-clinical studies; Therapeutic strategies; Tissue restoration

 

The collagen scaffold supports hiPSC-derived NSC growth and restricts hiPSC.

Front Biosci (Schol Ed). 2019 Mar 1;11:105-121.

Zychowicz M1, Pietrucha K2, Podobinska M1, Kowalska-Wlodarczyk M3, Lenart J4, Augustyniak J1, Buzanska L5.

Author information

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5 St, 02-106, Warsaw, Poland.

2 Department of Material and Commodity Sciences and Textile Metrology, Lodz University of Technology, Zeromskiego 116 St, 90-924, Lodz, Poland.

3 Oil and Gas Institute, National Research Institute, 25 A Lubicz St, 31-503 Cracow, Poland.

4 Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5 St, 02-106, Warsaw, Poland.

5 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5 St, 02-106, Warsaw, Poland, This email address is being protected from spambots. You need JavaScript enabled to view it..

 

Abstract

The human induced pluripotent stem cells (hiPSC) are one of the promising candidates as patient specific cell source for autologous transplantation or modeling of diseases. The collagen (Col) scaffolds have been shown suitable to create in vitro biomimetic microenvironment for human neural stem cells, but their ability to accommodate stem cells at different stages of neural differentiation has not been verified yet. In this paper we compare lineage related hiPSC during neural differentiation for their ability to colonize Col scaffold. We have also focused on modification of collagen physicochemical properties with improved mechanical and thermal stability, without loss of its biological activity. The hiPSC expressing markers of pluripotency (OCT4, SOX2, NANOG) after neural commitment are NESTIN, GFAP, PDGFR alpha, beta- TUBULIN III, MAP-2, DCX, GalC positive. We have shown, that Col scaffold was not preferable for hiPSC culture, while the neurally committed population after seeding on Col scaffolds revealed good adhesion, viability, proliferation, along with sustaining markers of neuronal and glial differentiation. The Col scaffold-based 3D culture of hiPSC-NSCs may serve as a research tool for further translational studies.

 

Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells.

Mol Neurobiol. 2019 Jun;56(6):4346-4363. doi: 10.1007/s12035-018-1368-2. Epub 2018 Oct 13.

Augustyniak J1, Lenart J2, Gaj P3, Kolanowska M4, Jazdzewski K3,4, Stepien PP5,6,7, Buzanska L8.

Author information

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

2 Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

3 Laboratory of Human Cancer Genetics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.

4 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.

5 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.

6 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

7 Centre of New Technologies, University of Warsaw, Warsaw, Poland.

8 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Bezafibrate (BZ) regulates mitochondrial biogenesis by activation of PPAR's receptors and enhancing the level of PGC-1α coactivator. In this report, we investigated the effect of BZ on the expression of genes (1) that are linked to different pathways involved in mitochondrial biogenesis, e.g., regulated by PPAR's receptors or PGC-1α coactivator, and (2) involved in neuronal or astroglial fate, during neural differentiation of hiPSC. The tested cell populations included hiPSC-derived neural stem cells (NSC), early neural progenitors (eNP), and neural progenitors (NP). RNA-seq analysis showed the expression of PPARA, PPARD receptors and excluded PPARG in all tested populations. The expression of PPARGC1A encoding PGC-1α was dependent on the stage of differentiation: NSC, eNP, and NP differed significantly as compared to hiPSC. In addition, BZ-evoked upregulation of PPARGC1A, GFAP, S100B, and DCX genes coexist with downregulation of MAP2 gene only at the eNP stage of differentiation. In the second task, we investigated the cell sensitivity and mitochondrial biogenesis upon BZ treatment. BZ influenced the cell viability, ROS level, mitochondrial membrane potential, and total cell number in concentration- and stage of differentiation-dependent manner. Induction of mitochondrial biogenesis evoked by BZ determined by the changes in the level of SDHA and COX-1 protein, and mtDNA copy number, as well as the expression of NRF1, PPARGC1A, and TFAM genes, was detected only at NP stage for all tested markers. Thus, developmental stage-specific sensitivity to BZ of neurally differentiating hiPSC can be linked to mitochondrial biogenesis, while fate commitment decisions to PGC-1α (encoded by PPARGC1A) pathway.

KEYWORDS:

Bezafibrate; Mitochondrial biogenesis; NSC; PGC-1α; PPAR’s; hiPSC

 

Species-specific models in toxicology: in vitro epithelial barriers.

Environ Toxicol Pharmacol. 2019 Aug;70:103203. doi: 10.1016/j.etap.2019.103203. Epub 2019 Jun 1.
Bertero A1, Augustyniak J2, Buzanska L2, Caloni F3.
Author information
1 Università degli Studi di Milano, Department of Veterinary Medicine (DIMEVET) Milan, Italy.
2 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
3 Università degli Studi di Milano, Department of Veterinary Medicine (DIMEVET) Milan, Italy. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it..
Abstract
Species-specific in vitro epithelial barriers represent interesting predictive tools for risk assessment evaluation in toxicological studies. Moreover, these models could be applied either as stand-alone methods for the study of absorption, bioavailability, excretion, transport, effects of xenobiotics, or through an Integrated Testing Strategy. The aim of this review is to give a comprehensive overview of in vitro species-specific epithelial barrier models from bovine, dog and swine. Bovine mammary epithelial barrier as a fundamental instrument for the evaluation of the toxicant excretion, the blood brain barrier as a useful first approach in toxicological and pharmacological studies, the porcine intestinal barrier, the canine skin barrier, and finally the pulmonary barrier from bovine and swine species are described in this review.
Copyright © 2019 Elsevier B.V. All rights reserved.
KEYWORDS:
Barriers; Species-specific; Toxicology; in vitro

Species-specific models in toxicology: in vitro epithelial barriers.

Environ Toxicol Pharmacol. 2019 Aug;70:103203. doi: 10.1016/j.etap.2019.103203. Epub 2019 Jun 1.

Bertero A1, Augustyniak J2, Buzanska L2, Caloni F3.

Author information

1        Università degli Studi di Milano, Department of Veterinary Medicine (DIMEVET) Milan, Italy.

2        Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

3        Università degli Studi di Milano, Department of Veterinary Medicine (DIMEVET) Milan, Italy. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Species-specific in vitro epithelial barriers represent interesting predictive tools for risk assessment evaluation in toxicological studies. Moreover, these models could be applied either as stand-alone methods for the study of absorption, bioavailability, excretion, transport, effects of xenobiotics, or through an Integrated Testing Strategy. The aim of this review is to give a comprehensive overview of in vitro species-specific epithelial barrier models from bovine, dog and swine. Bovine mammary epithelial barrier as a fundamental instrument for the evaluation of the toxicant excretion, the blood brain barrier as a useful first approach in toxicological and pharmacological studies, the porcine intestinal barrier, the canine skin barrier, and finally the pulmonary barrier from bovine and swine species are described in this review.

KEYWORDS:

Barriers; Species-specific; Toxicology; in vitro

 

Organoids are promising tools for species-specific in vitro toxicological studies.

J Appl Toxicol. 2019 Jun 5. doi: 10.1002/jat.3815. [Epub ahead of print]

Augustyniak J1, Bertero A2, Coccini T3, Baderna D4, Buzanska L1, Caloni F2

Author information

1 Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

2 Department of Veterinary Medicine (DIMEVET), Università degli Studi di Milano, Milan, Italy.

3 Laboratory of Clinical and Experimental Toxicology, Toxicology Unit, ICS Maugeri SpA-SB, IRCCS Pavia, Pavia, Italy.

4 Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Italy.

Abstract

Organoids are three-dimensional self-aggregating structures generated from stem cells (SCs) or progenitor cells in a process that recapitulates molecular and cellular stages of early organ development. The differentiation process leads to the appearance of specialized mature cells and is connected with changes in the organoid internal structure rearrangement and self-organization. The formation of organ-specific structures in vitro with highly ordered architecture is also strongly influenced by the extracellular matrix. These features make organoids as a powerful model for in vitro toxicology. Nowadays this technology is developing very quickly. In this review we present, from a toxicological and species-specific point of view, the state of the art of organoid generation from adult SCs and pluripotent SCs: embryonic SCs or induced pluripotent SCs. The current culture organoid techniques are discussed for their main advantages, disadvantages and limitations. In the second part of the review, we concentrated on the characterization of species-specific organoids generated from tissue-specific SCs of different sources: mammary (bovine), epidermis (canine), intestinal (porcine, bovine, canine, chicken) and liver (feline, canine).

KEYWORDS:

3D models; ESCs; iPSCs; organoids; spheroids; stem cells; toxicology

 

Reference Gene Validation via RT-qPCR for Human iPSC-Derived Neural Stem Cells and Neural Progenitors.

Mol Neurobiol. 2019 Mar 29. doi: 10.1007/s12035-019-1538-x. [Epub ahead of print]

Augustyniak J1, Lenart J2, Lipka G1, Stepien PP3, Buzanska L4.

Author information

1 Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinskiego Str., 02-106, Warsaw, Poland.

2 Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinskiego Str., 02-106, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

3 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 5a Pawinskiego Str., 02-106, Warsaw, Poland.

4 Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinskiego Str., 02-106, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

 

Abstract

Correct selection of the reference gene(s) is the most important step in gene expression analysis. The aims of this study were to identify and evaluate the panel of possible reference genes in neural stem cells (NSC), early neural progenitors (eNP) and neural progenitors (NP) obtained from human-induced pluripotent stem cells (hiPSC). The stability of expression of genes commonly used as the reference in cells during neural differentiation is variable and does not meet the criteria for reference genes. In the present work, we evaluated the stability of expression of 16 candidate reference genes using the four most popular algorithms: the ΔCt method, BestKeeper, geNorm and NormFinder. All data were analysed using the online tool RefFinder to obtain a comprehensive ranking. Our results indicate that NormFinder is the best tool for reference gene selection in early stages of hiPSC neural differentiation. None of the 16 tested genes is suitable as reference gene for all three stages of development. We recommend using different genes (panel of genes) to normalise RT-qPCR data for each of the neural differentiation stages.

KEYWORDS:

Gene expression reference panel; Neural Progenitor; Neural Stem Cells; Relative gene expression; human induced Pluripotent Stem Cell (hiPSC); quantitative real-time Polymerase Chain Reaction (RT-qPCR)

 

A Distinct Advantage to Intraarterial Delivery of 89Zr-Bevacizumab in PET Imaging of Mice With and Without Osmotic Opening of the Blood-Brain Barrier.

A Distinct Advantage to Intraarterial Delivery of 89Zr-Bevacizumab in PET Imaging of Mice With and Without Osmotic Opening of the Blood-Brain Barrier.

J Nucl Med. 2019 May;60(5):617-622. doi: 10.2967/jnumed.118.218792. Epub 2018 Oct 12.

Lesniak WG1, Chu C1,2, Jablonska A1,2, Du Y1, Pomper MG1, Walczak P1,2,3, Janowski M4,2,5.

Author information

1        Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins    University School of Medicine, Baltimore, Maryland.

2        Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.

3        Department of Neurosurgery, University of Warmia and Mazury, Olsztyn, Poland; and.

4        Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland This email address is being protected from spambots. You need JavaScript enabled to view it..

5        NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and common type of brain cancer. Five-year survival rates are below 12%, even with the most aggressive trimodal therapies. Poor blood-brain barrier (BBB) permeability of therapeutics is a major obstacle to efficacy. Intravenous administration of bevacizumab is the standard treatment for GBM. It has been recently demonstrated that a single intraarterial infusion of bevacizumab provides superior therapeutic outcomes in patients with recurrent GBM. Further GBM treatment benefits can be achieved through opening of the BBB before intraarterial infusion of bevacizumab. However, a rationale for intraarterial delivery and BBB opening when delivering antibodies is lacking. A method facilitating quantification of intraarterial delivery of bevacizumab is needed for more effective and personalized GBM treatment. Here, we demonstrate such a method using PET imaging of radiolabeled bevacizumab. Methods: Bevacizumab was conjugated with deferoxamine and subsequently radiolabeled with 89Zr. 89Zr-bevacizumab deferoxamine (89Zr-BVDFO) was prepared with a specific radioactivity of 81.4 ± 7.4 MBq/mg (2.2 ± 0.2 μCi/mg). Brain uptake of 89Zr-BVDFO on carotid artery and tail vein infusion with an intact BBB or with BBB opening with mannitol was initially monitored by dynamic PET, followed by whole-body PET/CT at 1 and 24 h after infusion. Th ex vivo biodistribution of 89Zr-BVDFO was also determined. Results: Intraarterial administration of 89Zr-BVDFO resulted in gradual accumulation of radioactivity in the ipsilateral hemisphere, with 9.16 ± 2.13 percentage injected dose/cm3 at the end of infusion. There was negligible signal observed in the contralateral hemisphere. BBB opening with mannitol before intraarterial infusion of 89Zr-BVDFO resulted in faster and higher uptake in the ipsilateral hemisphere (23.58 ± 4.46 percentage injected dose/cm3) and negligible uptake in the contralateral hemisphere. In contrast, intravenous infusion of 89Zr-BVDFO and subsequent BBB opening did not lead to uptake of radiotracer in the brain. The ex vivo biodistribution results validated the PET/CT studies. Conclusion: Our findings demonstrate that intraarterial delivery of bevacizumab into the brain across an osmotically opened BBB is effective, in contrast to the intravenous route.

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

KEYWORDS:

brain; drug delivery; endovascular; molecular imaging; nuclear medicine

 

Biodistribution of Glial Progenitors in a Three Dimensional-Printed Model of the Piglet Cerebral Ventricular System.

Biodistribution of Glial Progenitors in a Three Dimensional-Printed Model of the Piglet Cerebral Ventricular System.

Stem Cells Dev. 2019 Apr 15;28(8):515-527. doi: 10.1089/scd.2018.0172. Epub 2019 Mar 28.

Srivastava RK1,2, Jablonska A1,2, Chu C1,2, Gregg L3, Bulte JWM1,2, Koehler RC4, Walczak P1,2,5, Janowski M1,2,6.

Author information

1        Division of MR Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

2        Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

3        Visualization Core Laboratory, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

4        Department of Anesthesiology and Critical Care Medicine, Translational Tissue Engineering Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

5        Department of Neurology and Neurosurgery, University of Warmia and Mazury, Olsztyn, Poland.

6        NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Abstract

White matter damage persists in hypoxic-ischemic newborns even when treated with hypothermia. We have previously shown that intraventricular delivery of human glial progenitors (GPs) at the neonatal stage is capable of replacing abnormal host glia and rescuing the lifespan of dysmyelinated mice. However, such transplantation in the human brain poses significant challenges as related to high-volume ventricles and long cell migration distances. These challenges can only be studied in large animal model systems. In this study, we developed a three dimensional (3D)-printed model of the ventricular system sized to a newborn pig to investigate the parameters that can maximize a global biodistribution of injected GPs within the ventricular system, while minimizing outflow to the subarachnoid space. Bioluminescent imaging and magnetic resonance imaging were used to image the biodistribution of luciferase-transduced GPs in simple fluid containers and a custom-designed, 3D-printed model of the piglet ventricular system. Seven independent variables were investigated. The results demonstrated that a low volume (0.1 mL) of cell suspension is essential to keep cells within the ventricular system. If higher volumes (1 mL) are needed, a very slow infusion speed (0.01 mL/min) is necessary. Real-time magnetic resonance imaging demonstrated that superparamagnetic iron oxide (SPIO) labeling significantly alters the rheological properties of the GP suspension, such that, even at high speeds and high volumes, the outflow to the subarachnoid space is reduced. Several other factors, including GP species (human vs. mouse), type of catheter tip (end hole vs. side hole), catheter length (0.3 vs. 7.62 m), and cell concentration, had less effect on the overall distribution of GPs. We conclude that the use of a 3D-printed phantom model represents a robust, reproducible, and cost-saving alternative to in vivo large animal studies for determining optimal injection parameters.

KEYWORDS:

CSF; MRI; bioluminescence; brain; glial progenitors; iron oxide; ventricle

 

Challenges and Controversies in Human Mesenchymal Stem Cell Therapy.

Challenges and Controversies in Human Mesenchymal Stem Cell Therapy.

Stem Cells Int. 2019 Apr 9;2019:9628536. doi: 10.1155/2019/9628536. eCollection 2019.

Lukomska B1, Stanaszek L1, Zuba-Surma E2, Legosz P3, Sarzynska S3, Drela K1.

Author information

  1. NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
  2. Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
  3. Department of Orthopedics and Traumatology, 1st Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland.

Abstract

Stem cell therapy is being intensely investigated within the last years. Expectations are high regarding mesenchymal stem cell (MSC) treatment in translational medicine. However, many aspects concerning MSC therapy should be profoundly defined. Due to a variety of approaches that are investigated, potential effects of stem cell therapy are not transparent. On the other hand, most results of MSC administration in vivo have confirmed their safety and showed promising beneficial outcomes. However, the therapeutic effects of MSC-based treatment are still not spectacular and there is a potential risk related to MSC applications into specific cell niche that should be considered in long-term observations and follow-up outcomes. In this review, we intend to address some problems and critically discuss the complex nature of MSCs in the context of their effective and safe applications in regenerative medicine in different diseases including graft versus host disease (GvHD) and cardiac, neurological, and orthopedic disorders.

 

Concise Review: Mesenchymal Stem Cells: From Roots to Boost.

Concise Review: Mesenchymal Stem Cells: From Roots to Boost.

 Stem Cells. 2019 Apr 12. doi: 10.1002/stem.3016. [Epub ahead of print]

Andrzejewska A1, Lukomska B1, Janowski M1,2,3.

Author information

1        NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

2        Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3        Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

Abstract

It was shown as long as half a century ago that bone marrow is a source of not only hematopoietic stem cells, but also stem cells of mesenchymal tissues. Then the term of "mesenchymal stem cells" (MSCs) has been coined in early 1990s and over a decade later, the criteria for defining MSCs have been released by International Society for Cellular Therapy. The easy derivation from a variety of fetal and adult tissues and not demanding cell culture conditions made MSCs an attractive research object. It was followed by the avalanche of reports from preclinical studies on potentially therapeutic properties of MSCs, such as immunomodulation, trophic support and capability for a spontaneous differentiation into connective tissue cells, and differentiation into majority of cell types upon specific inductive conditions. Although ontogenesis, niche, and heterogeneity of MSCs are still under investigation, there is a rapid boost of attempts in clinical applications of MSCs, especially for a flood of civilization-driven conditions in so quickly aging societies in not only developed countries, but also very populous developing world. The fields of regenerative medicine and oncology are particularly extensively addressed by MSC applications, in part due to paucity of traditional therapeutic options for these highly demanding and costly conditions. There are currently almost 1,000 clinical trials from entire world registered at clinicalTrials.gov and it seems that we are starting to witness the snowball effect with MSCs becoming a powerful global industry; however, spectacular effects of MSCs in clinic still need to be shown. Stem Cells 2019.

© AlphaMed Press 2019.

KEYWORDS:

Clinical; Differentiation; History; Immunomodulation; Mesenchymal stem cells; Paracrine activity

 

Experimental Strategies of Mesenchymal Stem Cell Propagation: Adverse Events and Potential Risk of Functional Changes.

Experimental Strategies of Mesenchymal Stem Cell Propagation: Adverse Events and Potential Risk of Functional Changes.

Stem Cells Int. 2019 Mar 6;2019:7012692. doi: 10.1155/2019/7012692. eCollection 2019.

Drela K1, Stanaszek L1, Nowakowski A1, Kuczynska Z1, Lukomska B1.

Author information

  1. NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Abstract

Mesenchymal stem cells (MSCs) are attractive candidates for cell-based tissue repair approaches. Hundreds of clinical trials using MSCs have been completed and many others are still being investigated. For most therapeutic applications, MSC propagation in vitro is often required. However, ex vivo culture condition is not fully physiological and may affect biological properties of MSCs including their regenerative potential. Moreover, both cell cryopreservation and labelling procedure prior to infusion may have the negative impact on their expected effect in vivo. The incidence of MSC transformation during in vitro culture should be also taken into consideration before using cells in stem cell therapy. In our review, we focused on different aspects of MSC propagation that might influence their regenerative properties of MSC. We also discussed the influence of different factors that might abolish MSC proliferation and differentiation as well as potential impact of stem cell senescence and aging. Despite of many positive therapeutic effects of MSC therapy, one has to be conscious about potential cell changes that could appear during manufacturing of MSCs.

 

Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia-Ischemia: Potential Mechanism of Action.

Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia-Ischemia: Potential Mechanism of Action.

 Mol Neurobiol. 2019 Feb 14. doi: 10.1007/s12035-019-1518-1. [Epub ahead of print]

Jaworska J1, Zalewska T1, Sypecka J1, Ziemka-Nalecz M2.

Author information

1        Neurorepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland.

2        Neurorepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Neonatal hypoxic-ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi-sodium butyrate (SB)-would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia-ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor-CREB-in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF-TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia-ischemia.

KEYWORDS:

BDNF–TrkB pathway; CREB; ERK kinase; Neonatal hypoxia–ischemia; Neurogenesis

 

 

The Role of Glia in Canine Degenerative Myelopathy: Relevance to Human Amyotrophic Lateral Sclerosis.

The Role of Glia in Canine Degenerative Myelopathy: Relevance to Human Amyotrophic Lateral Sclerosis.

Mol Neurobiol. 2019 Jan 23. doi: 10.1007/s12035-019-1488-3. [Epub ahead of print]

Golubczyk D1, Malysz-Cymborska I1, Kalkowski L1, Janowski M2,3,4, Coates JR5, Wojtkiewicz J6, Maksymowicz W1, Walczak P7,8,9.

Author information

1        Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.

2        Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.

3        Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA.

4        Department of NeuroRepair, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

5        Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.

6        Department of Pathophysiology, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.

7        Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

8        Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA. This email address is being protected from spambots. You need JavaScript enabled to view it..

9        Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA. This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and grim prognosis. Over the last decade, studies on neurodegenerative diseases pointed on the role of glia in supporting the proper function of neurons. Particularly, oligodendrocytes were shown to be essential through myelin production and supplying axons with energy metabolites via monocarboxylate transporters (MCT). We have used dogs with naturally occurring degenerative myelopathy (DM) which closely resembles features observed in human ALS. We have performed two types of analysis of spinal cord tissue samples: histology and molecular analysis. Histology included samples collected from dogs that succumbed to the DM at different disease stages, which were compared to age-matched controls as well as put in the context of young spinal cords. Molecular analysis was performed on spinal cords with advanced DM and age-matched samples and included real-time PCR analysis of selected gene products related to the function of neurons, oligodendrocytes, myelin, and MCT. Demyelination has been detected in dogs with DM through loss of eriochrome staining and decreased expression of genes related to myelin including MBP, Olig1, and Olig2. The prominent reduction of MCT1 and MCT2 and increased MCT4 expression is indicative of disturbed energy supply to neurons. While Rbfox3 expression was not altered, the ChAT production was negatively affected. DM in dogs reproduces main features of human ALS including loss of motor neurons, dysregulation of energy supply to neurons, and loss of myelin, and as such is an ideal model system for highly translational studies on therapeutic approaches for ALS.

KEYWORDS:

ALS; Degenerative myelopathy; Demyelination; Disease model; Monocarboxylate transporters

 

SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS.

SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS.

Sci Rep. 2019 Jan 28;9(1):799. doi: 10.1038/s41598-018-37235-w.

Majchrzak M1, Drela K1, Andrzejewska A1, Rogujski P1, Figurska S2, Fiedorowicz M3, Walczak P4,5, Janowski M1,4, Lukomska B1, Stanaszek L6.

Author information

1        NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

2        Laboratory for Genetically Modified Animals, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

3        Department of Experimental Pharmacology and Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

4        Johns Hopkins University School of Medicine, Institute for Cell Engineering, Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA.

5        Department of Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, 10-719, Poland.

6        NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

The most recent research concerning amyotrophic lateral sclerosis (ALS) emphasizes the role of glia in disease development. Thus, one can suspect that the effective therapeutic strategy in treatment of ALS would be replacement of defective glia. One of the basic problems with human glial progenitors (hGRPs) replacement strategies is the time needed for the cells to become fully functional in vivo. The lifespan of most popular high copy number SOD1 mutant mice might be too short to acknowledge benefits of transplanted cells. We focused on developing immunodeficient rag2-/- model of ALS with lower number of transgene copies and longer lifespan. The obtained hSOD1/rag2 double mutant mice have been characterized. QPCR analysis revealed that copy number of hSOD1 transgene varied in our colony (4-8 copies). The difference in transgene copy number may be translated to significant impact on the lifespan. The death of long- and short-living hSOD1/rag2 mice is preceded by muscular weakness as early as one month before death. Importantly, based on magnetic resonance imaging we identified that mutant mice demonstrated abnormalities within the medullar motor nuclei. To conclude, we developed long-living double mutant hSOD1/rag2 mice, which could be a promising model for testing therapeutic utility of human stem cells.

 

Exchange-mode glutamine transport across CNS cell membranes

Neuropharmacology

Available online 8 March 2019

Invited review

Exchange-mode glutamine transport across CNS cell membranes

Jan Albrecht, Magdalena Zielińska

 

https://doi.org/10.1016/j.neuropharm.2019.03.003Get rights and content

Abstract

CNS cell membranes possess four transporters capable of exchanging Lglutamine (Gln) for other amino acids: the large neutral amino acid (LNAA) transporters LAT1 and LAT2, the hybrid basic amino acid (L-arginine (Arg), L-leucine (Leu)/LNAA transporter y+LAT2, and the L-alanine/L-serine/L-cysteine transporter 2 (ASCT2). LAT1/LAT2 and y+LAT2 are present in astrocytes, neurons and the blood brain barrier (BBB) - forming cerebral vascular endothelial cells (CVEC), while the location of ASCT2 in the individual cell types is a matter of debate. In the healthy brain, contribution of the exchangers to Gln shuttling from astrocytes to neurons and thus their role in controlling the conversion of Gln to the amino acid neurotransmitters l-glutamate (Glu) and γ-aminobutyric acid (GABA) and Gln flux across the BBB appears negligible as compared to the system A and system N uniporters. Insofar, except for the contribution of LAT1 to the maintenance of Gln homeostasis in the interstitial fluid (ISF), no well-defined CNS-specific function has been established for either of the three transporters in the healthy brain. The Gln-accepting amino acid exchangers appear to gain significance under conditions of excessive brain Gln load (glutaminosis). Excess Gln efflux across the BBB enhances influx into the brain of L-tryptophan (Trp). Excess of Trp is responsible for overloading the brain with neuroactive compounds: serotonin, kynurenic acid, quinolinic acid and/or oxindole, which contribute to neurotransmission imbalance accompanying hyperammonemia. In turn, alterations of y+LAT2-mediated Gln/Arg exchange and Arg uptake in astrocyte, modulate astrocytic nitric oxide synthesis and oxidative/nitrosative stress in ammonia-overexposed brain.

Keywords

Glutamine, Transport, Amino acid exchanger, Astrocyte, Blood-brain barier, Ammonia

 

 

 

 

Transfection with GLS2 Glutaminase (GAB) Sensitizes Human Glioblastoma Cell Lines to Oxidative Stress by a Common Mechanism Involving Suppression of the PI3K/AKT Pathway

Ewelina Majewska 1, JavierMárquez 2 , Jan Albrecht 1 and Monika Szeliga 1,*
1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland; This email address is being protected from spambots. You need JavaScript enabled to view it. (E.M.); This email address is being protected from spambots. You need JavaScript enabled to view it. (J.A.)
2 Canceromics Laboratory, Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain; This email address is being protected from spambots. You need JavaScript enabled to view it.
* Correspondence: This email address is being protected from spambots. You need JavaScript enabled to view it.; Tel.: +48-22-60-86-416
Received: 27 December 2018; Accepted: 17 January 2019; Published: 19 January 2019

Abstract: GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced. Previously, it was shown that transfection with a sequence encoding GAB, the main GLS2 isoform, decreased the survival, growth, and ability to migrate of human GBM cells T98G and increased their sensitivity towards an alkylating agent temozolomide (TMZ) and oxidative stress compared to the controls, by a not well-defined mechanism. In this study we report that GAB transfection inhibits growth and increases susceptibility towards TMZ and H2O2-mediated oxidative stress of two other GBM cell lines, U87MG and LN229. We also show that in GAB-transfected cells treated with H2O2, the PI3K/AKT pathway is less induced compared to the pcDNA-transfected counterparts and that pretreatment with PDGF-BB, an activator of AKT, protects GAB-transfected cells from death caused by the H2O2 treatment. In conclusion, our results show that (i) GAB suppresses the malignant phenotype of the GBM cells of different tumorigenic potentials and genetic backgrounds and (ii) the GAB-mediated increase of sensitivity to oxidative stress is causally related to the inhibition of the PI3K/AKT pathway. The upregulation of the GLS2 expression and the inhibition of the PI3K/AKT pathway may become a novel combined therapeutic strategy for anti-glioma preclinical investigations.
Keywords: GLS2 glutaminase; human glioblastoma; PI3K/AKT signaling pathway; oxidative stress.

Results Probl Cell Differ. 2018;66:207-230. doi: 10.1007/978-3-319-93485-3_9.

Bioengineering of the Human Neural Stem Cell Niche: A Regulatory Environment for Cell Fate and Potential Target for Neurotoxicity.
 
Buzanska L 1, Zychowicz M 2, Kinsner-Ovaskainen A 3.
 
Author information:

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

2 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

3 European Commission, Joint Research Centre, Directorate for Health Consumers and Reference Materials, Ispra, Italy.

ABSTRACT:

Human neural stem/progenitor cells of the developing and adult organisms are surrounded by the microenvironment, so-called neurogenic niche. The developmental processes of stem cells, such as survival, proliferation, differentiation, and fate decisions, are controlled by the mutual interactions between cells and the niche components. Such interactions are tissue specific and determined by the biochemical and biophysical properties of the niche constituencies and the presence of other cell types. This dynamic approach of the stem cell niche, when translated into in vitro settings, requires building up "biomimetic" microenvironments resembling natural conditions, where the stem/progenitor cell is provided with diverse extracellular signals exerted by soluble and structural cues, mimicking those found in vivo. The neural stem cell niche is characterized by a unique composition of soluble components including neurotransmitters and trophic factors as well as insoluble extracellular matrix proteins and proteoglycans. Biotechnological innovations provide tools such as a new generation of tunable biomaterials capable of releasing specific signals in a spatially and temporally controlled manner, thus creating in vitro nature-like conditions and, when combined with stem cell-derived tissue specific progenitors, producing differentiated neuronal tissue structures. In addition, substantial progress has been made on the protocols to obtain stem cell-derived cell aggregates such as neurospheres and self-assembled organoids.In this chapter, we have assessed the application of bioengineered human neural stem cell microenvironments to produce in vitro models of different levels of biological complexity for the efficient control of stem cell fate. Examples of biomaterial-supported two-dimensional and three-dimensional (2D and 3D) complex culture systems that provide artificial neural stem cell niches are discussed in the context of their application for basic research and neurotoxicity testing.
 
 
KEYWORDS:

Bioengineering; Neural stem cells; Neurotoxicity; Stem cell niche

Persistent Overexposure to N-Methyl-D-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes.

Neurotox Res. 2019 Jan;35(1):271-280. doi: 10.1007/s12640-018-9958-3. Epub 2018 Sep 15.

Skowrońska K1, Obara-Michlewska M1, Czarnecka A1, Dąbrowska K1, Zielińska M1, Albrecht J2.

Author information:

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

2      Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract

Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the functional astroglia-specific proteins, glutamine synthetase (GS), and the water channel protein aquaporin-4 (AQP4) and also reduces GS activity. Similar to rat astrocytes (Obara-Michlewska et al. Neurochem Int 88:20-25, 2015), the exposure of mouse astrocytes to NMDA also decreased the expression of the inward rectifying potassium channel Kir4.1. NMDA failed to elicit the effects in those cells incubated in the absence of Ca2+ and in those in which the GluN1 subunit of the NMDAR was silenced with GluN1 siRNA. The downregulation of GS, AQP4, and Kir4.1 observed in vitro may reflect NMDAR-mediated alterations of astrocytic functions noted in central nervous system pathologies associated with increased glutamate (Glu) release and excitotoxic tissue damage.

KEYWORDS:

Aquaporin 4; Astrocytes; Excitotoxicity; GluN1; Glutamine synthetase; Kir4.1; NMDA receptor

Cerebrovascular reactivity and cerebral perfusion of rats with acute liver failure: role of L-glutamine and asymmetric dimethylarginine in L-arginine-induced response.

J Neurochem. 2018 Dec;147(5):692-704. doi: 10.1111/jnc.14578. Epub 2018 Nov 6.

 Czarnecka A 1, Aleksandrowicz M 2, Jasiński K 3, Jaźwiec R 4, Kalita K 3, Hilgier W 1, Zielińska M 1.

Author information:

1   Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

2   Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

3   Department of Magnetic Resonance Imaging, Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland.

4    Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

Abstract:

Cerebral blood flow (CBF) is impaired in acute liver failure (ALF), however, the complexity of the underlying mechanisms has often led to inconclusive interpretations. Regulation of CBF depends at least partially on variations in the local brain L-arginine concentration and/or its metabolic rate. In ALF, other factors, like an increased concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and elevated level of L-glutamine, may contribute to CBF alteration. This study demonstrated strong differences in the reactivity of the middle cerebral arteries and their response to extravascular L-arginine application between vessels isolated from rats with thioacetamide (TAA)-induced ALF and control animals. Our results also showed the decrease in the cerebral perfusion in TAA rats measured by arterial spin labeling perfusion magnetic resonance. Subsequently, we aimed to investigate the importance of balance between the concentration of ADMA and L-arginine in the CBF regulation. In vivo, intraperitoneal L-arginine administration in TAA rats corrected: (i) decrease in cerebral perfusion, (ii) decrease in brain extracellular L-arginine/ADMA ratio and (iii) increase in brain L-glutamine concentration. Our study implicates that impaired vascular tone of cerebral arteries is most likely associated with exposure to high ADMA and L-glutamine levels resulting in limited availability of L-arginine and might be responsible for reduced cerebral perfusion observed in ALF.

KEYWORDS:

Acute liver failure; MRI-ASL; asymmetric dimethylarginine; cerebral blood flow; isolated middle cerebral artery

Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity.

Wilkaniec A1, Gąssowska-Dobrowolska M1, Strawski M2, Adamczyk A1, Czapski GA3.

Author information:

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

2 Laboratory of Electrochemistry, Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland.

3 Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5, 02-106, Warsaw, Poland. This email address is being protected from spambots. You need JavaScript enabled to view it..

 

ABSTRACT:

BACKGROUND:

Cyclin-dependent kinase 5 (Cdk5) belongs to the family of proline-directed serine/threonine kinases and plays a critical role in neuronal differentiation, migration, synaptogenesis, plasticity, neurotransmission and apoptosis. The deregulation of Cdk5 activity was observed in post mortem analysis of brain tissue of Alzheimer's disease (AD) patients, suggesting the involvement of Cdk5 in the pathomechanism of this neurodegenerative disease. However, our recent study demonstrated the important function of Cdk5 in regulating inflammatory reaction.

 

METHODS:

Since the role of Cdk5 in regulation of inflammatory signalling in AD is unknown, we investigated the involvement of Cdk5 in neuroinflammation induced by single intracerebroventricular (icv) injection of amyloid beta protein (Aβ) oligomers in mouse. The brain tissue was analysed up to 35 days post injection. Roscovitine (intraperitoneal administration) was used as a potent Cdk5 inhibitor. The experiments were also performed on human neuroblastoma SH-SY5Y as well as mouse BV2 cell lines treated with exogenous oligomeric Aβ.

 

RESULTS:

Our results demonstrated that single injection of Aβ oligomers induces long-lasting activation of microglia and astrocytes in the hippocampus. We observed also profound, early inflammatory response in the mice hippocampus, leading to the significant elevation of pro-inflammatory cytokines expression (e.g. TNF-α, IL-1β, IL-6). Moreover, Aβ oligomers elevated the formation of truncated protein p25 in mouse hippocampus and induced overactivation of Cdk5 in neuronal cells. Importantly, administration of roscovitine reduced the inflammatory processes evoked by Aβ in the hippocampus, leading to the significant decrease of cytokines level.

 

CONCLUSIONS:

These studies clearly show the involvement of Cdk5 in modulation of brain inflammatory response induced by Aβ and may indicate this kinase as a novel target for pharmacological intervention in AD.

 

KEYWORDS:

Alzheimer’s disease; Amyloid beta; Cdk5; Cytokines; Gene expression; Neuroinflammation