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.

Nrf2 is a transcription factor with a well-characterized role in protection against oxidative stress. Nrf2 activation is impaired in both aging and neurodegeneration. We have previously shown that Nrf2 is protective against Alzheimer’s disease and that therapeutic metal delivery complexes are protective against neurodegeneration via Nrf2 induction. Little is known about the importance of Nrf2 for mitochondrial function in neurodegenerative disease. A better understanding of these processes may in the future lead to improved treatments for neurodegeneration and ways to increase health and longevity.

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
  • The role of Nrf2 in astrocytes during neurodegeneration
  • The importance of Nrf2 in mitochondria
  • Mitochondrial degradation: mechanisms and consequences in neurodegenerative diseases
  • Biometal homeostasis in neurodegenerative diseases
  • Neurogenesis alterations in disease

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 the patients. Animal models of disease include the APdE9 and 5xFAD mouse models of Alzheimer’s disease, and the Cln5 mouse model of neuronal ceroid lipofuscinoses. We also use models of peripheral inflammation and use aged mice with co-morbid conditions.

We employ a range of behavioral tests and magnetic resonance imaging 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

Selected publications

  1. 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.
  2. Malm T, Loppi S, Kanninen KM. Exosomes in Alzheimer’s disease. Neurochem Int. 2016 Apr 27. pii: S0197-0186(16)30061-4.
  3. 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.
  4. 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.
  5. 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.
  6. Korhonen P, Kanninen KM, Lehtonen Š, Lemarchant S, Puttonen KA, Oksanen M, Dhungana H, Loppi S, Pollari E, Wojciechowski S, Kidin I, García-Berrocoso T, Giralt D, Montaner J, Koistinaho J, Malm T (2015). Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation. Brain Behav Immun. 2015 Jun 22. doi: 10.1016/j.bbi.2015.06.013.
  7. Grubman A, Pollari E, Duncan C, Caragounis A, Blom T, Volitakis I, Wong A, Cooper J, Crouch PJ, Koistinaho J, Jalanko A, White AR, Kanninen KM. Deregulation of biometal homeostasis: the missing link for neuronal ceroid lipofuscinoses? Metallomics. 2014 Apr;6(4):932-43.
  8. 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.
  9. Parker SJ, Koistinaho J, White AR, Kanninen KM. Biometals in rare neurodegenerative disorders of childhood. Front Aging Neurosci. 2013 Mar 25;5:14.
  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.