Neuroinflammation Research //


Acute and slowly degenerative diseases, such as stroke, Alzheimer’s disease (AD) are both without a cure and although etiologically very distinct, they share common pathological hallmarks. One of the main shared feature of these diseases is neuroinflammation. Whilst neuroinflammation can be a contributor to the nearby neuronal death by increased secretion of neurotoxic molecules by glial cells, microglia and astrocyte can also function to promote neuronal recovery through secretion of neurotrophic factors and through their potential phagocytic capacity. Moreover, peripheral inflammation may contribute to neuroinflammation in diseased conditions.

Traditionally cytokines and chemokines secreted by cells taking part on neuroinflammation have been thought to underlie the intercellular communication. We are now focusing on novel determinants of this communication, exosomes. Exosomes are small lipid-bilayer microvesicles secreted out of the cells and form a natural communication route between diverse cell types. Exosomes contain proteins, metabolites and nucleid acids capable of influencing the function of the recipient cells. Exosomes appear to play a major role not only in disease development but they also represent potentially novel avenues for biomarkers and therapy.

Understanding glial functions, especially microglia and astrocytes and the interplay between peripheral inflammation and neuroinflammation is the key for development of therapeutics aimed at modulating inflammation for CNS benefit. 

We believe that proper engagement of beneficial microglial functions offers means to combat neurodegenerative diseases. Our research aims at elucidating how peripheral inflammation impacts neuroinflammation in CNS diseases. In addition, we aim at deciphering the secreted cellular mediators of neuroinflammatory processes. Our research aims at finding not only disease specific but also common mechanism of neuroinflammation and how these can be taken advantage to modulate neuroinflammation for CNS benefit.

Research interests

  • To unravel disease specific and common mechanisms of neuroinflammation
  • To identify the secreted cellular mediators, such as exosomes that contribute to neuroinflammation
  • To identify how neuroinflammation is regulated by non-conding RNAs
  • To identify novel treatment strategies to modulate neuroinflammation for CNS benefit

Methodological approach

We utilize several both transgenic and surgically induced animal models of neurodegeneration, especially Alzheimer’s disease and stroke. We carry out research using APP/PS1 and 5XFAD mice to model Alzheimer’s disease and permanent and transient stroke models. In addition, we use Cln5-knockout mice modeling neuronal ceroid lipofuscinoises and surgically induced in vivo models of neuroinflammation. We use aged animals and animals with co-morbidities entailing peripheral inflammation. The functional outcome is measured by using various behavioral tests with long term follow up time.

We also analyze human stroke and Alzheimer’s disease patient tissues. We develop novel human Alzheimer’s disease patient derived induced pluripotent stem cell (iPSC) based models of inflammation that we culture in 2D or 3D co-cultures. In addition, we have vast experience on primary murine cellular models  including neuronal, microglial and astrocyte cultures as well as co-culture models (Fig 1). We are also utilizing neuronal progenitor cell cultures for assessment of neuronal and astrocytic differentiation (Fig. 2, 3). We take advantage of virus mediated gene transfer methods both in vivo and in vitro and analyze cellular responses using flow cytometry and confocal microscopy.

Fig. 1 Neuron-microglia co-culture model for assessing inflammation induced neuronal death. Primary neurons stained with MAP2 and BV2 cells with Iba-1.

Fig. 2. Neuronal progenitor cells grown in spheres. Differentiating neurons stained with Tuji-1 (red).

Fig. 3. Neuronal progenitor cells grown in spheres and stained for GFAP positive astrocytes (green).

Main achievements

We were the first to demonstrate that bone marrow derived cells infiltrate into Alzheimer’s disease transgenic mouse brain and take part in neuroinflammatory reactions (Malm et al., Neurobiology of Disease, 2005). We have recently shown that modulation of microglial activation by peroxisome proliferator activator delta (PPARdelta) agonist leads to rapid clearance of beta-amyloid from the brain of Alzheimer’s disease transgenic mice (Malm et al., J Neuroinflammation 2015).

We have shown that peripheral LPS induced inflammation is detrimental for the outcome of ischemic stroke especially in aged animals (Dhungana et al., Aging Cell 2013). In addition, we were the first to demonstrate that modulation of peripheral inflammation towards Th2 is beneficial in a mouse model of contusion spinal cord injury through promotion of CNS alternative macrophage activation (Pomeshchik Y et al., Brain Behav Immun 2015). Thereafter we have shown that shifting of peripheral inflammatory reactions towards Th2 is beneficial also in a mouse model of ischemic stroke (Korhonen et al., Brain Behav Immun 2015).


Emil Aaltonen Foundation
Academy of Finland
Finnish Cultural Foundation

Selected publications


  1. Malm T, Loppi S, Kanninen K. Exosomes in Alzheimer's disease (2016). Neurochem Int. Apr 27. pii: S0197-0186(16)30061-4. doi: 10.1016/j.neuint.2016.04.011
  2. 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.
  3. Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, Ransohoff RM, Lamb BT, Landreth G Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease. J Neuroscience 2015. Apr 22; 35(16)6532-43
  4. Pomeshchik Y, Kidin I, Korhonen P, Savchenko E, Wojciechowski S, Kanninen K, Koistinaho J, Malm T (2014). Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav Immun. 2015 Feb;44:68-81.
  5. Malm T, Mariani M, Donovan LJ, Neilson L, Landreth GE. Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer's disease through inhibition of inflammation. J Neuroinflammation 2015. Jan 16;12:7
  6. Malm T, Jay T and Landreth G. (2014) The evolving biology of microglia in Alzheimer’s diseases. Neurotherapeutics. Jan;12(1):81-93.
  7. Rolova T, Puli L, Magga J, Dhungana H, Kanninen K, Wojciehowski S, Salminen A, Tanila H, Koistinaho J, Malm T. Complex regulation of acute and chronic neuroinflammatory responses in mouse models deficient for nuclear factor kappa B p50 subunit. Neurobiol Dis. 2014 Apr;64:16-29.
  8. Dhungana H*, Malm T*, Denes A, Valonen P, Wojciechowski S, Magga J, Savchenko E, Humphreys N, Grencis R, Rothwell N, Koistinaho J (2013). Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection. Aging Cell. 12, 842-850. * Equal contribution
  9. Dhungana H, Rolova T, Savchenko E, Wojciechowski S, Savolainen K, Ruotsalainen AK, Sullivan PM, Koistinaho J, Malm T (2013). Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele. J Neuroinflammation. 10, 102-2094-10-102
  10. Karkkainen V, Magga J, Koistinaho J, Malm T (2012). Brain environment and Alzheimer's disease mutations affect the survival, migration and differentiation of neural progenitor cells. Curr Alzheimer Res. 9, 1030-1042.