Jari Koistinaho, PhD, MD
Professor of Stem Cell Research, Professor of Pharmacology, Project Coordinator
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
I. The research group.
The Laboratory of Molecular Brain Research investigates molecular mechanisms of neurodegeneration focusing on models of acute neurodegeneration (stroke, spinal cord injury) and chronic neurodegeneration (Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis).
We use a number of in vivo and in vitro models of these diseases including genetically modified mouse strains.
In addition, we have generated human induced pluripotent stem cells (iPSCs) from patients with neurodegenerative, psychiatric or cardiac diseases as well as prepared primary cultures of certain human and mouse cells to be used as research tools.
The idea is to investigate the role of key factors, including enzymes, cytokines, receptors and their functions that are involved in immune response and inflammation, oxidative stress or cell death at the molecular and cellular level and verify their significance in the pathogenesis.
We also obtain human body fluids, blood cells and autopsy material to further understand the clinical relevance of these factors.Our current research approaches include characterization of AD pathology in transgenic mouse lines as well as in iPSC lines derived from patients with AD. We pay special attention in dysfunctional interaction of endoplasmic reticulum and mitochondria and inflammatory pathways mediated by non-neuronal cells. Humanizing the mouse models by transplanting human iPSC-derived cells, especially astrocytes, is a novel approach to increase the translational value of rodent disease models.
II. Participation in the MADGIC project.
Our task in the JPND MADGIC project is to participate in generation of human neural stem cells through iPSCs and direct conversion of somatic cells, from fAD and sAD patients and healthy controls. The generation, labeling and purifying disease relevant neural subtypes from fAD and sAD patients and healthy controls and establishment of 3D systems will be carried out.
Further aim is to set-up platforms to uncover cell and non-cell autonomous mechanisms of AD in vitro and in vivo, which would allow to determine synaptic alterations under pathological conditions and provide better understanding of inflammation in AD, eventually contributing to the new target identification.
Utilization of these platforms will uncover pathological changes in neurons, astrocytes, oligodendrocytes and microglia-like cells, with genetic background as variable and by interaction with environmental factors (LPS-triggered injection, Ischemia-induced while matter damage, diet, aging and Aβ toxicities. Examination of behavioral changes in humanized chimeric mice will be carried out.
Importantly, 3D cultures of neuronal cells generated from fAD and sAD patients and humanized chimeric animals will be used to study repurposing of EMEA/FDA approved drugs and to determine the neuroprotective role of viral gene therapy-based systems.
III. Key publications relevant for the project
1. Pomeshchik et al. (2014) Transplanted human iPSC-derived neural progenitor cells do not promote functional recovery of pharmacologically immunosuppressed mice with contusion spinal cord injury. Cell Transplantation, Sep 8.
2. Kaärkkaäinen et al (2014) Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells, 32:1904-1916.
3. Pomeshchik et al., Does Nrf2 gene transfer facilitate recovery after contusion spinal cord injury? Antioxid Redox Signal. 2014;20:1313-23.
4. Karkkainen et al., Brain environment and Alzheimer's disease mutations affect the survival, migration and differentiation of neural progenitor cells. Curr Alzheimer Res. 2012;9:1030-42.
5. Kanninen K et al, (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 106(38):16505-10.