Neuroinflammation Research //
Science

Scope

Acute and slowly degenerative diseases, such as stroke, Alzheimer’s disease (AD) and Parkinson’s disease are all without a cure and although etiologically very distinct, they share common pathological hallmarks. One of the main shared features of these diseases is neuroinflammation geared by activated glia. Instead of supporting neuronal connectivity as they do in the healthy brain, glial cells get activated, secrete neurotoxic molecules and contribute to neuronal malfunctions.

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, extracellular vesicles (EVs). EVs are small lipid-bilayer microvesicles secreted out of the cells and form a natural communication route between diverse cell types. EVs contain proteins, metabolites and nucleic acids capable of influencing the function of the recipient cells. EVs appear to play a major role not only in disease development but they also represent potentially novel avenues for biomarkers and therapy.

In depth understanding of 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 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 form a functional fingerprint of microglia-neuron crosstalk in health and disease
  • To identify secreted mediators of this intercellular crosstalk, such as EVs
  • To identify how neuroinflammation is regulated at the level of non-conding RNAs
  • To identify novel treatment strategies to modulate neuroinflammation for CNS benefit

Methodological approach

We use novel, human-based models to find new therapeutic targets for the disease benefit and to discover novel biomarkers. We develop new human iPSC-based models including microglia and immunocompetent organoids and use living human brain tissue biopsies. We investigate cellular responses using various omics approaches, electrophysiology and microscopy techniques.

In addition, we take advantage of animal modelling with functional outcomes. 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. The functional outcome is measured by using various behavioral tests with long term follow up time.

Main achievements

By using human iPSC-based models, we have shown APOE4/4 genotype has profound impact on several aspects of microglila functionality, whereas PSEN1ΔE9 and APPswe trigger minor alterations (Konttinen et al., Stem Cell Reports 2019). Instead, in iPSC-derived astrocytes PSEN1ΔE9 impairs fatty acid oxidation (Konttinen et al., Glia 2019). PPARdelta agonism is capable of both correcting this impairment (Konttinen et al., Glia 2019), and it also 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).

Funding

Horizon 2020
Business Finland
Academy of Finland
ERANET Neuron
JPND-cofund
Emil Aaltonen Foundation
Finnish Cultural Foundation
Olav Thon Foundation
Juselius Foundation

Selected publications

  1. Konttinen, e Castro Cabral-da-Silva, Ohtonen S, Wojciechowski S, Shakirzyanova S, Caligola S, Giugno R, Ishchenko Y, Hernández D, Fazaludeen F, Eamen S, Gómez Budia M, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, W. Hewitt A, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pébay S, Koistinaho J, Ooi L,  Malm T. PSEN1ΔE9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Reports 2019, Oct 8;13(4):669-683 DOI: https://doi.org/10.1016/j.stemcr.2019.08.004
  2. Singh Y, Leinonen H, Fazaludeen F, Jaronen, M, Debbie G, Buckley N, Byts N, Oksa P, Jalkanen K, Iqbal I, Huuskonen M, Savchenko E, Keksa-Goldsteine V, Chew S, Myllyharju J, Tanila H, Ooi L, Koistinaho J, Kanninen K and Malm T. Loss of Cln5 leads to altered Gad1 expression and deficits in interneuron development in mice. Human Molecular Genetics. 2019, Jul 11, pii: ddz165. doi: 10.1093/hmg/ddz165.
  3. Turunen T, Roberts T, Laitinen P, Väänänen M-A, Korhonen P, Malm T, Ylä-Herttuala S, and Turunen M. Changes in nuclear and cytoplasmic microRNA distribution following hypoxic stress”. Scientific Reports 2019, Jul 17;9(1):10332
  4. Ezzat K, Pernemalm M, Pålsson S, Roberts TC, Järver P, Dondalska A, Bestas B, Sobkowiak MJ, Levänen B, Sköld M, Thompson EA, Kari OK, Lajunen T, Ishchenko Y, Malm T, Wood MJA, Power UF, Masich S, Lindén A, Sandberg JK, Lehtiö J, Spetz AL, EL Andaloussi S. The Viral Protein Corona Directs Viral Pathogenesis and Amyloid Aggregation. Nature Communications 2019, May 27;10(1):2331.
  5. Konttinen H, Gureviciene I*, Oksanen M*, Grubman A, Loppi, Huuskonen MT, Korhonen P, Lampinen T, Keuters M, Belaya I, Tanila H, Kanninen KM, Goldsteins G, Landreth G, Koistinaho J, Malm T. PPARβ/δ-agonist GW0742 Ameliorates Dysfunction in Fatty Acid Oxidation in PSEN1ΔE9 Astrocytes. Glia 2019, Jan;67(1):146-159
  6. Loppi S, Kolosowska N, Kärkkäinen O, Korhonen P, Huuskonen M, Grubman A, Dhungana H, Wojciechowski S, Pomeshchik Y, Giordano M, Kagechika H, White A, Auriola S, Koistinaho J, Landreth G, Hanhineva K, Kanninen K, Malm T. HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage. Brain Behav Immun 2018 Oct; 73:670-681.
  7. Dhungana H, Huuskonen M, Jaronen M, Lemarchant S, Ali S, Keksa-Goldsteine V Goldsteins G, Kanninen K, Koistinaho J, Malm T. Sulfosuccinimidyl oleate sodium is neuroprotective and alleviates stroke induced neuroinflammation. J Neuroinflammation, 2017, Dec 4;14(1)237.
  8. 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.
  9. Pomeshchik Y, Puttonen KA, Kidin I, Ruponen M, Lehtonen S, Malm T, Akesson E, Hovatta O, Koistinaho J. Transplanted human iPSC-derived neural progenitor cells do not promote functional recovery of pharmacologically immunosuppressed mice with contusion spinal cord injury. Cell Transplant 2015;24(9):1799-812
  10. 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