Molecular Brain Research // Science

We focus on models of acute neurodegeneration (stroke, spinal cord injury) and chronic neurodegeneration (Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis).

We have also generated human induced pluripotent stem cells (iPSCs) from patients with neurodegenerative, psychiatric or cardiac diseases.

Another of our major findings is the therapeutic potential of minocycline, a tetracycline derivative, in brain diseases (patented in 2001).

Stroke

Stroke is the third leading cause of death after cancer and heart disease. It is also a major cause of serious and long-term disability. While stroke is considered a significant cause of death in elderly populations, hypoxic ischemia is a common cause of damage to the fetal and neonatal brain.

Even a short lasting hypo-perfusion of the brain or obstruction of cerebral arteries can result quickly in irreversible brain damage. Importantly, the following ischemic brain damage may evolve for days or weeks after acute insult. Thus this delayed neuronal death can be potentially interfered by therapy.

Immune response and inflammation is represent one of the major processes that are responsible for the delayed damage that occur after stroke. Therefore, it is important to clarify the role of peripheral immune cells, microglial cells and their activation mechanisms during and after acute stroke. Such research can be carried out by using clinically relevant animal models and in vitro cell culture models. Another important aspect under investigation is the role of infiltrating leukocytes as well as neurogenesis. We collaborate with small biotech companies to develop and test novel chemical entities or biomolecules that could be beneficial in stroke. Recent studies also indicate that brain lymphatic system may play a role in stroke pathology and recovery.

Collaboration

  • Prof. Olli Gröhn , A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Assoc. Prof. Tarja Malm, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Prof. Perttu Lindsberg, Department of Clinical Neurosciences, Helsinki University Central Hospital
  • Prof. Markus Schwaninger, Heidelberg University
  • Prof. Denis Vivien, University of Caen Basse Normandie
  • Dr. Adam Denes, Hungarian Academy of Sciences
  • Prof. Kari Alitalo, University of Helsinki
  • Large European consortia of stroke research, including 15 different laboratories

Recent publications

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Spinal cord injury

Spinal cord injury (SCI) is very serious injury that can cause permanent impairment of motor and sensory functions of limbs, or even complete paralysis due to damaged axons.

The acute pathology includes axon cut, bleeding and swelling caused by displaced bone fragments. Consequently, swelling causes ischemia. In addition, immune reactions and inflammation, excitotoxicity, free radical attack and apoptosis are thought to contribute to the damage in SCI.

Basically, there are four key principles of spinal cord repair research:

  • protecting surviving nerve cells from further damage,
  • replacing damaged nerve cells,
  • stimulating the regrowth of axons and targeting their connections appropriately, and
  • retraining neural circuits to restore body functions.

There is strong evidence that infiltrating inflammatory cells, endogenous glia and oxidative stress play an important role in SCI pathogenesis.

Our aim is to identify some of the key elements of immune system, inflammation and oxidative stress that could serve as therapeutic targets in SCI. Our therapeutic approaches include novel pharmacological agent, cell transplantation and gene transfer. For transplantation we use monocytes as well human iPSC-derived cells alone or in combination with pharmacological therapy to enhance survival, migration and integration of transplanted cells into the CNS tissue.

Collaboration

  • Prof. Denis Vivien, University of Caen Basse Normandie
  • Prof. Anna-Liisa Levonen, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Assoc. Prof. Tarja Malm, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland

Recent publications

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Alzheimer's Disease (AD)

Alzheimer's disease (AD) is the major form of dementia in the aging population and the fourth leading cause of death amongst the elderly. The pathological hallmarks of AD are the presence of amyloid beta (Aβ) containing plaques and neurofibrillary tangles. A small portion of AD cases is caused by autosomal dominant mutations in APP or presenilin genes that lead to elevation of highly fibrillogenic form of Aβ.

In addition to neurodegeneration, Aβ is thought to be the major trigger of chronic inflammation in the AD brain, which is mainly mediated by microglia and astrocytes.

The relationship of microglia to plaque development in AD is still an open question:

  • microglia may take part in the synthesis, processing or catabolism of AAP and Aβ,
  • microglia can process APP and Aβ to fibrillar forms that readily aggregate in amyloid plaques,
  • microglia play a role in the clearance of Aβ deposits by phagocytosing or degrading the deposited Aβ.

Under physiological circumstances, astrocytes are chaperoning neurons to their synaptic sites, maintaining the functional integrity of the synapse and contributing to extracellular matrix protein. Upon activation, astrocytes can secrete numerous growth factors, a variety of matrix proteins, adhesion factors, and factors associated with inflammation, such as prostaglandins, leukotrienes, thromboxanes, complement factors, proteases and protease inhibitors. Recently, adult astrocytes have been reported to have a high capacity to clear Aβ peptides in an apoE dependent manner.

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.

Collaboration

  • Prof. Heikki Tanila, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Prof. Anna-Liisa Levonen, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Assoc. Prof. Tarja Malm, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Prof. Mikko Hiltunen, School of Medicine, University of Eastern Finland
  • Dr. Anthony White, University of Melbourne
  • Dr. Patrick Sullivan, Duke University, North Carolina
  • Dr. Akihiko Takashima, Riken Brain Science Institute
  • Dr. Poul Hyttel, University of Copenhagen
  • Prof. Laurent Roybon and Prof. Gunnar Gouras, Lund University, Sweden
  • Prof. Frank Edenhofer, University of Würtzburg, Germany
  • Prof. Michael Heneka, University of Bonn, Germany
  • Prof. Claire Rampon, University of Toulouse, France
  • Prof. Dora Brites, University of Lisbon, Portugal

Recent publications

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Amyotrophic Lateral Sclerosis (ALS)

ALS is a lethal, chronic motor neuron disease that causes selective motor neuron degeneration affecting both the upper and lower motor neurons of the spinal cord, brain stem, and cortex.

The progressive degeneration of motor neurons in ALS leads eventually to death of the patients, which happens in average 5 years after the diagnosis. The exact mechanisms of motor neurons death in ALS are not known, but excitotoxicity, apoptosis and inflammation are involved. Mutations in superoxide dismutase 1 (SOD1) gene, have been found in about 20% of families with familial ALS. The existing ALS therapy is limited to symptomatic relief, prevention of complications, and maintenance of maximal optimal function and optimal quality of life.

Recent studies indicate that non-neuronal cells, astrocytes and microglia, have an important role in pathogenesis of ALS. In animal models, in which neurons with the SOD1 mutation are surrounded by glia with normal genes, the glia is able to stave off the disease. On the other hand, when mutant glial cells encircle genetically normal motor neurons, the motor neurons are attacked by the glia (astrocytes and microglia), which may mount a lethal inflammatory response against the neurons.

Thus, we aim to identify novel pathways taking place in neurons and non-neuronal cells in ALS models and cells to test whether such pathways could be pharmacologically interfered to achieve a therapeutic benefit.

Collaboration

  • Prof. Rashid Giniatullin, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Assoc. Prof. Tarja Malm, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Dr. Anthony White, University of Melbourne
  • Prof. Su-Chun Zhang, University of Wisconsin, USA
  • Prof. L. van den Bosch, Department of Neurology, University of Leuven, Medical School. Belgium.

Recent publications

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Induced pluripotent stem cells in neurodegeneration research

Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cells that can be generated from adult somatic cells. Upon appropriate physiological or experimental conditions, these cells can be induced to differentiate into certain specific cell types, such as neurons or astrocytes. Over the years our laboratory derived patient-specific cells from AD, PD, ALS, schizophrenia and patients with criminal behaviour and substance abusers.

We investigate the potential of human iPSCs to model human brain diseases. While brain pathology from diseased patients show late stages of this neurodegenerative diseases, patient specific-derived iPSCs have a potential to model early pre-symptomatic stages. Therefore using iPSCs as a disease model may help to understand disease mechanisms and opens new avenues for the development of effective clinical intervention.

Collaboration

  • Prof. Pasi Tavi, Dr. Michael Courtney and Dr. Nihay Laham-Karam, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Assoc. Prof. Tarja Malm, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
  • Prof. Jari Tiihonen, Dr. Outi Hovatta and Dr. Elisabet Åkesson, KI, Stockholm
  • Prof. Su-Chun Zhang, University of Wisconsin, Madison
  • Prof. Petr Dvořák, Masaryk University, Brno
  • Dr. Juha Rinne and Dr. Matti Viitanen, University of Turku
  • Dr. Poul Hyttel, University of Copenhagen
  • Dr. Laurent Roybon, University of Lund
  • Dr. K. Fukuda, Keio University, Japan
  • Dr. Maria A. Lagarkova and Dr. Sergey L. Kiselev, Vavilov Institute of General Genetics, Moscow

Recent publications

  • Creation of a library of induced pluripotent stem cells from Parkinsonian patients. Holmqvist, S.*, Lehtonen, Š.*, Chumarina, M., Puttonen, KA., Azevedo, C., Lebedeva, O., Ruponen, M., Oksanen, M., Collin, A., Goldwurm, S., Meyer, M., Lagarkova, M., Kiselev, S., Koistinaho, J., Roybon, L. Nature Publishing Group Parkinsonʾs disease 2016.  * equal contribution

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Identification of drug molecules as a potentially therapeutic agents for brain diseases

One of the major findings of our laboratory is the therapeutic potential of minocycline, a tetracycline derivative, in brain diseases (patented in 2001).

Minocycline, as well another semisynthetic tetracycline, doxycycline, are highly protective in clinically relevant models of stroke and global ischemia. Our further studies indicated that minocycline reduces activation of microglia, the main immune cells in the brain), thereby reducing the secondary brain damage.

We identified p38 MAPK pathway as one of the possible target of minocycline. In addition, we showed that cerebrospinal fluid from patients with patients with ALS, a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, is toxic to cultured spinal cord neurons and that minocycline exerts a significant neuroprotective effect against this toxicity.

To date, minocycline has been demonstrated to have a beneficial effect in a wide variety of models of neuropathological conditions, including brain and spinal cord trauma, hemorrhagic stroke, AD, PD, ALS, multiple sclerosis (MS), Huntington's disease, neonatal hypoxia-ischemia, ototoxicity, glaucoma, HIV, encephalopathy, prion disease and pain.

Besides anti-inflammatory effects, minocycline may provide its beneficial effects by antiapoptotic functions. In one of our projects, we are investigating the direct neuroprotective mechanisms of minocycline to reveal the novel therapeutic targets in treating brain diseases.

Recent publications

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