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Factsheet by Bente Finsen

Group name: Finsen-Group
Group leader: Bente Finsen
Group members: 3 PhD students, 1 postdoc, and 2 part time technicians.
Department & University/Hospital/Other: Department of Neurobiology Research, Institute of Molecular Medicine, SDU
Funding sources: The Danish Multiple Sclerosis Society, The Danish Alzheimer Society, The Veluxfoundation, The Danish Research Agency, The Lundbeckfoundation, SDU2020.

Description of research:
Our research aims to understand how our immune system, particularly the innate microglia, contributes to protect and strengthen the neuronal network in acute and chronic CNS-disease.
1. Neuro-glial interactions in Alzheimer's disease (AD). We wish to understand why microglia fail to clear A-beta in AD, and whether this relates to microglial dysfunction/degeneration. Microglial failure in AD may involve both glial- and neuronally-expressed signaling molecules, such as TNF and IL-1, as well as the neurotransmitter serotonin (5-HT), which promotes microglial process motility and upregulates expression of A-beta-degrading enzymes. In the case of TNF and IL-1, data are currently being extracted from cytokine knocked-out APP/PS1 mice and controls. In the case of 5- HT, we have characterised the expression of 5-HT receptors on primary microglia cells, and are now examining mo- lecular signaling pathways downstream of the 5-HT2a/b-receptors in A-beta-stimulated microglia, followed by functional studies. Studies on the effects of selective 5-HT reuptake inhibitors and genetic inactivation of tryptophan hydrox- ylase-2 on A-beta-load in APP/PS1 mice are nearing completion.

2. Proteomic profiling of AD and non-AD brain and APP/PS1 mouse brain. Proteomics suggest that an astrocyte- produced cytokine/growth factor, along with IgG are particularly abundant in the neocortex from AD cases. These findings are being validated by immunohistochemistry in AD and non-AD tissue. Findings of Tau hyperphosphorylati- on at pSer404 by proteomics in APP/PS1 cortical tissue are currently being evaluated to decipher the role of A as a driver of Tau-pathology. In addition, proteomic studies of tissue from APP/PS1 transgenics treated with bacterially- derived lipopolysaccharide (LPS) have indicated that LPS stimulates the complement pathways, an observation that might underlie the observed reduction in A-beta-load in the neocortex of the same animals.

3. Regulation of microglial cytokine production. Microglial cells are heterogeneous in terms of their production of the functionally important cytokines TNF, IL-1alfa/beta, and L-1Ra. Cytokines, such as TNF and IL-1Ra, and potentially IL- 6, which have neuroprotective and pro-regenerative functions in stroke, have been shown also to have complex func- tions in AD and multiple sclerosis (MS). Work in progress focuses on the posttranscriptional regulation of TNF in an MS-context. These studies involve RNA-Seq on IFN-gamma-stimulated microglia for circular, linear, and microRNA, following by functional analysis and in vivo validation in brain tissue from MS models and patients with MS.

4. Myelination/remyelination. We have a long-standing interest in understanding how myelin-reactive T-cells appear to stimulate the remyelination of denuded axons by stimulating the oligodendrocyte precursor cells (OPCs). We have identified a set of genes, which we show are expressed in OPCs in vivo. We now study the role of one of the identified genes in OPC differentiation and myelination processes. Moreover, we have identified the genome-wide active binding sites in OPCs and oligodendrocytes of the transcription factor Nkx2.2, which has a well-defined role in myelination. These studies involved ChIP-seq and transcript profiling of Nkx2.2-/- mice, and siRNA-knock down of Nkx2.2 in rat OPC, and are in the pipeline for publication.

The projects outlined above heavily depend on both national and international collaborations.

Key publications (last 10 years):
47 original papers, 3 reviews, 3 methods papers

Neuro-glial interactions in AD (incl. microglial cell dynamics)
1. Wirenfeldt M, Dissing-Olesen L, Babcock AA, Nielsen M, Meldgaard M, Zimmer J, Azcoitia I, Leslie RGQ, Dag- næs-Hansen F, Finsen B (2007) Population control of resident and immigrating microglia by mitosis and apopto- sis. Am J Pathol 171:1-31.
2. Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyadenylation and miR-34 family members regulate Tau expression. J Neurochem 127:739-49.
3. Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A (2014) Accelerated microglial pathology is asso- ciated with Aβ plaques in mouse models of Alzheimer's disease. Aging Cell 13:584-95.
4. Khan AM, Babcock AA, Saeed H, Myhre CL, Kassem K, Finsen B (2015) Telomere dysfunction reduces microg- lial numbers without fully inducing an aging phenotype. Neurobiol Aging 36:2164-75.
5. Babcock AA, Ilkjær L, Clausen BH, Villadsen B, Dissing-Olesen L, Bendixen ATM, Lyck L, Lambertsen KL, Fin- sen B (2015) Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice. Brain Beh Immun. 48:86-101.
6. Olesen LØ, Bouzinova E, Severino M, Sivasaravanaparan M, Hasselstrøm JB, Finsen B*, Wiborg O* (2016) Be- havioural phenotyping of APPswe/PS1dE9 mice: Age-related changes and effect of long-term paroxetine treatment. PLoS One. 11(11):e0165144.
7. Metaxas A, Vaitheeswaran R, Jensen KT, Darvesh S, Finsen B. Reduced serotonin transporter levels and in- flammation in the midbrain raphe of APP/PS1 mice, without local deposition of plaques or tangles. In submission.
8. Olesen LØ, Sivasaravanaparan M, Severino M, Babcock AA, Bouzinova EV, West MJ, Wiborg O*, Finsen B*
(2017) Neuron number and neurogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine. Neurobiol. Aging. PMID: 28461249.
9. Von Linstow CU, Severino M, Metaxas A, Waider J, Lesch KP, Gramsbergen JB, Finsen B (2017) Effect of age- ing and Alzheimer’s disease-like pathology on brain monoamines in mice. Neurochem. Int. PMID: 28414094.
10. Von Linstow CU, Waider J, Grebing M, Metaxas A, Lesch KP, Finsen B. Serotonin augmentation therapy by
11. escitalopram has subtle or no effect on amyloid-β levels in early stage Alzheimer's-like disease in mice. In sub- misssion/revision.
12. Babcock AA, Ilkjær L, Wirenfeldt M, Krøigård T, Myhre CL, Khan AM, Dissing-Olesen L, Darvesh S, Jensen MS, West MJ, Finsen B. Beta-amyloid induces apoptosis of phagocytic microglia and macrophages. In sub- misssion/revision.

Proteomic profiling in AD and AD mouse models
13. Lyck L, Dalmau Santamaria I, Pakkenberg B, Chemnitz J, Schrøder HD, Finsen B*, Gundersen HJG (2009) An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator-design with sub-sampling. J Neurosci Meth 182:143-856. *Corresponding author
14. Kempf SJ, Metaxas A, Ibáñez-Vea M, Darvesh S, Finsen B, Larsen MR (2016) An integrated proteomics ap- proach shows synaptic plasticity changes in an APP/PS1 Alzheimer´s mouse model. Oncotarget 7:33627-48.
15. Jensen P, Myhre CL, Lassen P, , Khan AM, Babcock AA, Finsen B*, Larsen MR*, Kempf SJ. Elucidation of the molecular network of TNF in neurons in neuroinflammation and neural plasticity. Oncotarget. In revision.

Regulation of microglial (neuroprotective) cytokine production Cerebral Ischemia/Stroke
16. Clausen BH*, Lambertsen KL*, Babcock AA, Holm T, Dagnaes-Hansen F, Finsen B (2008) Interleukin-1β and
tumor necrosis factor-a are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflam. 5:46. *Shared 1st authorship.
17. Lambertsen KL, Clausen BH, Babcock A, Gregersen R, Fenger C, Nielsen HH, Haugaard LS, Wirenfeldt M, Niel- sen M, Dagnaes-Hansen F, Bluethmann H, Færgeman NJ, Meldgaard M, Deierborg T, Finsen B (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 29:1319-1330.
18. Lambertsen KL, Deierborg T, Gregersen R, Clausen BH, Wirenfeldt M, Nielsen HH, Dalmau I, Diemer NK, Dag- naes-Hansen F, Johansen FF, Keating A, Finsen B (2011) Differences in origin of reactive microglia in bone mar- row chimeric mouse and rats after transient global ischemia. J Neuropathol Exp Neurol 70:481-494.
19. Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B (2016) Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta Neuropathol. 131:775-91.
20. Madsen PM, Clausen BH, Degn M, Thyssen S, Kristensen LK, Svensson M, Ditzel N, Finsen B, Deierborg T, Brambilla R, Lambertsen KL (2015) Genetic ablation of soluble tumor necrosis factor with preservation of mem- brane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia. J Cereb Blood Flow Metab. Oct 19. pii: 0271678X15610339.
21. Clausen B, Degn M, Martin N, Couch Y, Karimi L, Ormhøj M, Mortensen ML, Gredal H, Gardiner C, Sargent II, Szymkowski DE, Petit GH, Deierborg T, Finsen B, Anthony D, Lambertsen K (2015) Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. J Neuroinflam 11:203.
22. Gredal H, Thomsen BB, Boza-Serrano A, Garosi L, Rusbridge C, Anthony D, Møller A, Finsen B, Deierborg T, Lambertsen KL, Berendt M (2016) Interleukin-6 is increased in plasma and cerebrospinal fluid of community dwell- ing domestic dogs with acute ischaemic stroke. NeuroRep 28:134-140.
23. Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B (2016) Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta Neuropathol. 131:775-91.
24. Grønhøj MH, Clausen BH, Fenger C, Lambertsen KL, Finsen B. Intravenously administered IL-6 improves func- tional outcome after experimental stroke in C57BL/6 mice and is neuroprotective in IL-6 knock out mice. Brain Beh. Immun. In revision.
Posttranscriptional regulation
25. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384-8.
26. Venø MT, Hansen TB, Venø ST, Clausen BH, Grebing M, Finsen B, Holm IE, Kjems J (2015) Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol. 16:245.
27. Venø MT, Venø ST, Rehberg K, van Asperen J, Clausen BH, Holm IE, Pasterkamp I, Finsen B, Kjems J (2017) Cortical morphogenesis during embryonic development is regulated by miR-34c and miR-204. Feb 9;10:31.

Myelination/remyelination & multiple sclerosis
28. Nielsen HH, Ladeby R, Fenger C, Toft-Hansen H, Babcock AA, Owens T, Finsen B (2009) Enhanced microglial clearance of myelin debris in T cell infiltrated central nervous system. J Neuropathol Exp Neurol 68:845-856.
29. Drøjdahl N*, Nielsen HH*, Gardi J, Wree A, Peterson AC, Nyengaard JR, Eyer J, Finsen B (2010) Axonal plastici- ty elicits long-term changes in oligodendroglia and myelinated fibers. Glia 58:29-42. *Shared 1st authorship.
30. Nielsen HH, Toft-Hansen H, Lambertsen KL, Owens T, Finsen B (2011) Stimulation of adult oligodendrogenesis by myelin specific T-cells. Am J Pathol 179:2038-41.
31. Grebing MM, Nielsen HH, Fenger CD, Jensen KT, von Linstow CU, Clausen BH, Söderman M, Lambertsen KL, Thomassen M, Kruse TA, Finsen B (2016) Myelin specific T cells induce interleukin-1beta expression in activated microglia in zones of axonal degeneration. Glia 64:407-24.
32. Dionne N, Dib S, Finsen B, Denarier E, Tanja Kuhlmann T, Drouin R, Kokoeva M, Hudson TJ, Kathy Siminovitch K, Friedman HC, Peterson AC (2016) Functional organization of an mbp enhancer exposes striking transcriptional regulatory diversity within myelinating glia. Glia 64:175-94.
33. Fenger CD, Thomassen M, Abdulla SA, Larsen M, Kuhlmann T, Kotter MR, Kruse TA, Emery B, Finsen B. Ge- nome-wide identification of Nkx2.2 targets in oligodendrocyte-lineage cells reveals numerous novel target genes involved in a broad range of cellular activities. In submission/revision.

Key collaborations:
Prof. Martin Røssel Larsen, Ctr. Proteomics, Inst. Biochem. & Mol. Biol., SDU (proteomics) Prof. Jørgen Kjems, iNano, Inst. Mol. Biol., Aarhus University (AaU), Aarhus (RNAomics)
Prof. Torben Kruse, Human Genetics, Odense University Hospital (OUH), Odense (array analysis)
Prof. Poul Hyttel, Veterinary Medicine, Dpt. Anat, Physiol., Biochem., Copenhagen Univ. (AD, stem cell biol.) Senior scientist, Ove Wiborg, CFIN, Aarhus Univ. Hospital, Aarhus (AD, small animal behavior)
Chief consultant, PhD Helle Klingenberg Iversen, Rigshospitalet, Glostrup Hospital (stroke)

Prof. Klaus-Peter Lesch, Dpt. Psych., Würzburg Univ. Hospital, Würzburg, Germany (5-HT biology) Prof. Sultan Darvesh, Dalhousie Univ., & The Maritime Brain Tissue Bank, Halifax, Canada (AD) Prof. Tanja Kuhlmann, Dpt. Neuropath., Münster Univ. Hospital, Münster, Germany (MS)
Prof. Jessica Teeling, Southampton Univ., Southampton, United Kingdom (neuroinflammation in AD) Assoc. prof. Ben Emery, Dpt. Anat. & Neurosci. Univ. Melbourne, Melbourne, Australia

From originally being an entirely histology- and morphometry-based laboratory, my research group today uses inte- grated approaches that include different types of molecular biology and protein chemical techniques, cell cultivation-, isolation-, and characterization-techniques, pharmacology (ligand binding), high resolution anatomy, as well as rodent behavior. The laboratory has outstanding expertise in in situ hybridization techniques. Proteomics and RNAomics are performed on a collaborative basis.

Facilities available to the research group: EM-microscopy (Dpt. Pathology, OUH), Confocal microscopy (IMM, assoc. prof. S. Moestrup), Small animal behavioral suite (IMM, assoc. prof. KL Lambertsen), Flowcytometry (IMM, assoc. prof. S Hansen), Array Ctr. (Human Genetics, OUH (prof. T Kruse), Radioactivity lab (IMM, Autoradiography/cell har- vester, Seniorpostdoc. A Metaxas).