Neurobiology of Disease
//Science

Populations around the world are rapidly aging due to increasing life expectancy and declining fertility rate. Conditions that cause progressive neuronal dysfunction remain one of the leading causes of disability in the Western world. Despite extensive research, the actual causes of neurodegeneration remain largely unclear. It is of utmost importance to identify common and disease-specific factors that relate to disease causes and pave way for novel interventions. Our main goal is to understand the mechanisms that lead to neurodegenerative disease and to identify novel therapeutic approaches for these diseases.

Major research topics

  • Transcellular and intercellular communication in neurodegenerative diseases
  • Mitochondrial degradation: mechanisms and consequences in neurodegenerative diseases
  • Neurogenesis alterations in disease
  • Interplay between environmental factors and brain health
  • The importance of Nrf2 in mitochondria

Research methods

We utilize several in vitro and in vivo models of neurodegenerative disease.  In vitro models include murine primary neurons, neuronal progenitor cells, astrocytes, and microglia, cultured alone or in 2D or 3D co-cultures. We also utilize human cells and tissues from Alzheimer’s disease patients. Animal models of disease include the APdE9 and 5xFAD mouse models of Alzheimer’s disease. We also use models of peripheral inflammation aged mice with co-morbid conditions.

We employ a range of behavioral tests to measure the outcome of therapeutic interventions in mouse models. We also utilize confocal imaging, ex vivo slice cultures and sophisticated gene transfer technologies in our research. Techniques including immunocytochemistry, Western blotting and quantitative RT-PCR are in routine use in our research.

 
Figure 1: A high magnification confocal image shows the punctate pattern of  mitochondria in neuronal cells.
 

Figure 2: Fluorescence image of a murine neuronal progenitor sphere culture model used in our research.

Funding

The Academy of Finland
Emil Aaltonen Foundation Finland
The Sigrid Juselius Foundation
The Finnish Cultural Foundation
The Yrjö Jahnsson foundation

Selected publications

  1. Belaya I, Masataka S, Chen T, Giniatullin R, Kanninen KM, Atalay M, Kumagai S. Long-term exercise protects against cellular stresses in aged mice. Oxid Med Cell Longev. Accepted 22/1/2017.
  2. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen S, Gubert-Olive M, Shakirzyanova A, Leskelä S, Sarajärvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang S-U, Kanninen KM, Hämäläinen RH, Koistinaho J. PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. Stem Cell Rep. 2017 Dec 12;9(6):1885-1897.
  3. Savchenko E, Singh Y, Konttinen H, Lejavova K, Mediavilla Santos L, Grubman A, Kärkkäinen V, Keksa-Goldsteine V, Naumenko N, Tavi P, White AR, Malm TM, Koistinaho J, Kanninen KM. Loss of CLN5 causes altered neurogenesis in a childhood neurodegenerative disorder. Dis Model Mech. 2017 Sep 1;10(9):1089-1100.
  4. Leinonen H, Keksa-Goldsteine V, Ragauskas S, Kohlmann P, Singh Y, Savchenko E, Puranen J, Malm T, Kalesnykas G, Koistinaho J, Tanila H, Kanninen KM. Retinal degeneration in a mouse model of Cln5 disease is associated with compromised autophagy. Sci Rep 2017 accepted for publication 6.4.2017
  5. Huuskonen MT, Loppi S, Dhungana H, Keksa-Goldsteine V, Lemarchant S, Korhonen P, Wojciechowski S, Pollari E, Valonen P, Koponen J, Takashima A, Landreth G, Goldsteins G, Malm T, Koistinaho J, Kanninen KM. Bexarotene targets autophagy and is protective against thromboembolic stroke in aged mice with tauopathy. Sci Rep.2016 Sep 14;6:33176.
  6. Liddell JR, Lehtonen S, Duncan C, Keksa-Goldsteine V, Levonen A-L, Goldsteins G, Malm T, White AR, Koistinaho J, Kanninen KM. Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes. J Neuroinflamm. 2016 Feb 26;13(1):49.
  7. Kanninen KM, Bister N, Koistinaho J, Malm T (2015). Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 2015 Oct 13. pii: S0925-4439(15)00292-6.
  8. Kanninen KM, Pomeshchik Y, Leinonen HM, Malm T, Koistinaho J, Levonen A-L (2015). Applications of the Keap1-Nrf2 System for Gene and Cell Therapy. Free Rad Biol Med. 2015 Jul 8.
  9. Kärkkäinen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen A-L, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J. Nrf2 regulates neurogenesis and protects neural progenitor cells against Ab toxicity. Stem Cells Jul;32(7):1904-16.
  10. Kanninen K, Heikkinen R, Malm TM, Rolova T, Kuhmonen S, Leinonen H, Ylä-Herttuala S, Tanila H, Koistinaho M, Levonen A-L, Koistinaho J. 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. 2009 Sep 22;106(38):16505-10.