Research profile

The mission of the launched in 2014 laboratory is translation of discoveries from basic neuroscience to clinical trials. The Laboratory conducts its own research and provides the core-facility services for investigators from the Nencki Institute and other scientific and R&D institutions.

Our research focuses on molecular mechanisms of aging-related neurodegenerative diseases, mainly of Alzheimer’s disease (AD), which increasingly becomes one of the main crisis in the demographically ageing societies. The current treatments are inadequate because of the unclear AD pathogenesis and  mechanisms of progression. Our studies aim at elucidation of early molecular and cellular mechanisms of AD for identification of new therapeutic targets and non-invasive biomarkers, especially  for the early, pre-dementia AD stage. We are particularly interested in the regulation of the cell cycle and apoptosis in neurodegeneration and carcinogenesis, two main aging-related pathologies, and their relationships. The processes underlying AD are being studied at the level of gene expression, epigenomic regulation by microRNA, protein signaling, as well as at cellular and behavioral levels, using standard and newly developed by us animal and cellular AD models. We also investigate systemic changes in AD, mainly in human blood cells and plasma (biobank of over 100 lymphocyte lines from AD patients and non-demented age-matched control subjects).

A line of research lead by Grazyna Niewiadomska (PhD, DSc) aims to understand mechanisms involved in neural ageing and possible reversal of brain dysfunctions induced by aging. Towards this end, we implement new experimental protocols and conduct longitudinal studies using rats and transgenic mice models of AD and Parkinson’s disease (PD). We attempt to link cellular and behavioral levels of the brain processes present during physiological and pathological ageing. We develop quantitative approaches to the study of behavior which enable analysis of the relationships between the elements of a given behavioral proxies. In collaboration with TauRx Therapeutics Ltd,  we develop novel treatments, animal models and diagnostic procedures for the tauopathic diseases and assessment of toxicology, safety pharmacology, pharmacokinetics and behavioral effects of novel potential therapeutic compounds.

Current research activities

• Alterations in protein signaling and in microRNA regulation in the immune cells in blood from AD patients – role in AD pathogenesis and biomarker potential
• Search for non-invasive blood-based early AD biomarkers in blood cells and plasma
• Cell cycle and apoptosis regulation in peripheral cells from AD patients and in the derived reprogrammed neuronal progenitors and  mature neurons
• Signaling pathways and microRNAs affecting Tau protein aggregation and phosphorylation
• Mutated Presenilin1 and associated signaling pathways in cellular responses to oxidative stress in AD
• Development of novel mouse models of sporadic AD and correlation of AD biomarkers in human and AD mouse models
• Preclinical evaluation of novel potential anticancer therapeutics: mechanisms of cellular activity, pharmacokinetics, activity in mouse xenotransplantation cancer models
• Behavioral, morphologic and biochemical evaluation of the cholinotrophic system in two transgenic mouse lines developing Alzheimer-type (TgL1) and frontotemporal dementia-type (TgL66) tauopathy
• Cholinergic anabolism and signaling
• Age-dependent structural reorganization of cytoskeleton, microtubule transport and post-translational modifications of microtubule associated proteins during physiological ageing and neurodegenerative diseases
• Profiling age-related cognitive impairments in memory tasks
• Evaluation of factors determining neuroprotective effect of physical training using MPTP and TgL62 mice model of PD
• Development of novel treatments for neurodegenerative diseases: testing in animal models and assessment of drug safety and pharmacology.

Core facility activities

• Comprehensive preclinical in vitro and in vivo testing of safety and activity of potential new therapeutic substances for diseases of the nervous system, as well as for cancer, in accordance with the principles of Good Laboratory Practice (GLP):
• Consultations for experimental design and data analysis
• Activity testing of substances in cell cultures: cytotoxicity/cell survival (IC50), analysis of apoptosis, proliferation, cell cycle
• Study of active substances’ mechanism of activity in cell cultures: mRNA, miRNA and protein cellular levels
• Maintenance of laboratory mice in experiments
• Development and analysis of mouse models of neurodegenerative diseases and cancer
• Activity testing of potential neuroprotective or anticancer substances in mouse models of diseases
• Toxicological studies: histological preparation & histopathological analysis
• Pharmacokinetic assays
• Profiling cognitive impairments in memory tasks

UE Horizon 2020 FETOPEN grant at the Nencki Institute

Prof. Urszula Wojda is a member of an international consortium that has received a EU Horizon 2020 grant in the FETOPEN: Research & Innovation Action, Novel Ideas for Radically New Technologies competition. The aim of the consortium’s research is to develop new strategies for the treatment and diagnosis of Alzheimer’s disease based on studies of glycobiological alterations in AD. The “ArrestAD” project received the highest possible evaluation of reviewers (15/15).

The consortium of the “ArrestAD” project includes the following entities:

Consortium leader: University of Paris Est Créteil FR

• THE UNIVERSITY OF LIVERPOOL UK
• STICHTING KATHOLIEKE UNIVERSITEIT NL
• INSTYTUT BIOLOGII DOSWIADCZALNEJ IM. M. NENCKIEGO POLSKIEJ AKADEMII NAUK PL
• FUNDACION DE INVESTIGACION DEL CANCER DE LA UNIVERSIDAD DE SALAMANCA ES
• ASSISTANCE PUBLIQUE – HOPITAUX DE PARIS FR
• UNIVERSITAT AUTONOMA DE BARCELONA ES
• SCREENCELL Company

Prof. Urszula Wojda with her group from the Laboratory of Preclinical Studies of Higher Standard of the Neurobiology Centre at the Nencki Institute examines the relationships between genetic and proteomic factors of AD and changes of glycosaminoglycans in blood cells, as a basis for developing new strategies for the early diagnosis of AD. Blood samples for the research are provided by Prof. Thomas Gabryelewicz’s team from the Alzheimer’s Ward of the Central Clinical Hospital of the Ministry of the Interior and Administration in Warsaw.

http://cordis.europa.eu/project/rcn/207479_en.html

Selected publications

Wojsiat J, Zoltowska KM, Laskowska-Kaszub K, Wojda U. Oxidant/antioxidant imbalance in Alzheimer’s disease: therapeutic and diagnostic prospects. Oxidative Medicine and Cellular Longevity 2018:643586 (2018).

Wojsiat J, Laskowska-Kaszub K, Alquézar C, Białopiotrowicz E, Esteras N, Zdioruk M, Martin-Requero A, Wojda U. Familial Alzheimer’s Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 54(7):5683-5698 (2017)

Nagaraj S, Laskowska-Kaszub K, Dębski K, Wojsiat J, Dąbrowski M, Gabryelewicz T, Kuźnicki J, Wojda U. Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects. Oncotarget 8(10):16122-16143. The article featured on the cover (2017)

Mietelska-Porowska A., Wojda U. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers. Journal Immunology Research, ID 4626540, http://doi.org/10.1155/2017/4626540, (2017)

Niewiadomski W, Palasz E, Skupinska M, Zylinski M, Steczkowska M, Gasiorowska A, Niewiadomska G, Riedel G. TracMouse: A computer aided movement analysis script for the mouse inverted horizontal grid test. Sci Rep. 6:39331. doi: 10.1038/srep39331 (2016)

Koss DJ, Robinson L, Mietelska-Porowska A, Gasiorowska A, Sepčić K, Turk T, Jaspars M, Niewiadomska G, Scott RH, Platt B, Riedel G. Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits. Cell Mol Life Sci. 72(23):4613-32. doi: 10.1007/s00018-015-1949-4 (2015)