Stem cells models for studies of neurodegenerative diseases

Research focus

Our research activities are focused on disease modeling using induced pluripotent stem cells (iPSC) from patients and their CRISPR-Cas9 gene edited controls. Our research focus is on Alzheimer’s disease (AD), Frontotemporal dementia (FTD) and glaucoma.

Within AD and FTD we are investigating cell type specific pathologies in neurons, astrocytes and microglia. We are especially keen on understanding overlapping dysfunctions amongst different types of dementia and identification of key players in disease pathways. We believe that comprehensive understanding of such molecular commonalities may provide opportunities for novel interventions that are beneficial for an array of related diseases facilitating cost effective drug development. Explorations of disease pathways instead of disease-linked proteins will not only further the knowledge of disease development and progression, but also provide novel angles and targets for drug development. This part of our research is embedded in the BrainStem and NeuroStem projects (for more information: https://brainstem.dk/).

Within glaucoma we are specifically interested in the degeneration of retinal ganglion cells (RGCs) and their trophic support of Mueller cells (MCs). We are investigating this intrinsic inter-relation of MCs and RGCs in close collaboration with the clinic and Professor MSO Miriam Kolko.

Current projects

Our main research focus is on Frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Here we differentiate our cellular models into neurons, astrocytes and microglia and assess cellular phenotypes compared to their isogenic controls. BrainStem and NeuroStem (Innovation Foundation Denmark) support the disease in the dish modelling of both FTD and AD.We are particularly interested in the inflammatory component of neurodegeneration and investigate the role of specific single nucleotide polymorphisms (SNPs) related to the innate immune system in sporadic AD funded by Novo Nordisk Foundation(GliAD).

Additionally, we are investigating the consequences and treatment options in rare childhood epilepsies in collaboration with Rikke Møller at the Danish epilepsy center. This project implements CRISPR/Cas9 editing of healthy iPSC to generate loss and gain of function mutations in CACNA1A Novo Nordisk Foundation(PREMED).

Recently a Lundbeck collaborative project was awarded to Martin Røssel Larsen   https://lundbeckfonden.com/en/researchstories/mini-brains-to-shed-light-on-nervous-disorders in which I am co-applicant and partner together with Madelaine Lancester. Within this grant we will make several iPSC lines of schizophrenia patients and analyse their cerebral organoids.

Our glaucoma research is currently focusing on generation of RGCs in 3D optic cups and this work is supported by the Danish Ophthalmology Society via Miriam Kolko. 

Furthermore, we are collaborating with Poul Hyttel on a project to evaluate the dog as a model for AD research and compare iPSC derived neurons from dogs with canine cognitive deficits (CCD) to the human AD iPSC derived neurons (funded by the Dansk Forskningsråd, PI Poul Hyttel). Last but not least, we are collaborating with Hans Wandall and Jakob Barslev Sørensen on glycolysation changes in AD and Epilepsy, respectively. Both are funded via Lundbeck Foundation.

Dog induced pluripotent stem cell (iPSC) models for Alzheimer’s disease 

(FP2, The Danish Council for Independent Research/Production and Technological Sciences). Our overall hypothesis is that that domestic (pet) dogs with naturally occurring dementia offer significant advantages to existing experimental animal models for investigating Alzheimer’s disease (AD). We develop the dog model at the cellular and molecular level by finding commonalities between disease phenotype in iPSC-derived neurons from CCD dogs and human AD patients.

EggSphere

(FP1, The Danish Council for Independent Research/Natural Sciences) investigates the function of the oocyte’s nucleolus in embryonic development. The pig, in which the egg’s morphology and biology resembles its human counterpart, will be used to study the content of the nucleolus as well as the developmental competence conveyed by this structure.

Research Funding

Selected Publications

• Schmidt SI, Bogetofte H, Ritter L, Agergaard JB, Hammerich D, Kabiljagic AA, Wlodarczyk A, Lopez SG, Sørensen MD, Jørgensen ML, Okarmus J, Serrano AM, Kristensen BW, Freude K, Owens T, Meyer M (2021). Microglia-Secreted Factors Enhance Dopaminergic Differentiation of Tissue- and iPSC-Derived Human Neural Stem Cells. Stem Cell Reports

• Frederiksen HR, Doehn U, Tveden-Nyborg P, Freude K. (2021). Non-immunogenic Induced Pluripotent Stem Cells, a Promising Way Forward for Allogenic Transplantations for Neurological Disorders. Frontiers in Genome Editing

• Aldana BI, Zhang Y, Jensen P, Chandrasekaran A, Christensen SK, Nielsen TT, Nielsen JE, Hyttel P, Larsen MR, Waagepetersen HS, Freude K. (2020). Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia. Mol Brain

• Haukedal H, Freude K (2019). Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. J Mol Biol
• Vohra R, Aldana BI, Skytt DM, Freude K, Waagepetersen H, Bergersen LH, Kolko M. (2018). Essential Roles of Lactate in Muller Cell Survival and Function.  Mol Neurobiol
• Ochalek A, Mihalik B, Avci HX, Chandrasekaran A, Teglasi A, Bock I, Giudice ML, Tancos Z, Molnar K, Laszlo L, Nielsen JE, Holst B, Freude K, Hyttel P, Kobolak J, Dinnyes A. (2017). Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther 9(1):90.
• Aldana, B.I., Zhang, Y., Lihme, M.F., Bak, L.K., Nielsen, J.E., Holst, B., Hyttel, P., Freude, K.K., Waagepetersen, H.S., (2017) Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: A novel approach to study metabolism in human neurons. Neurochem Int.
• Zhang, Y., Schmid, B., Nikolaisen, N.K., Rasmussen, M.A., Aldana, B.I., Agger, M., Calloe, K., Stummann, T.C., Larsen, H.M., Nielsen, T.T., Huang, J., Xu, F., Liu, X., Bolund, L., Meyer, M., Bak, L.K., Waagepetersen, H.S., Luo, Y., Nielsen, J.E., Consortium, F.R., Holst, B., Clausen, C., Hyttel, P., Freude, K.K., (2017) Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. Stem Cell Reports 8, 648-658.
• Aldana, B.I., Zhang, Y., Lihme, M.F., Bak, L.K., Nielsen, J.E., Holst, B., Hyttel, P., Freude, K.K., Waagepetersen, H.S., (2017) Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: A novel approach to study metabolism in human neurons. Neurochem Int
• Zhou, S., Ochalek, A., Szczesna, K., Avci, H.X., Kobolak, J., Varga, E., Rasmussen, M., Holst, B., Cirera, S., Hyttel, P., Freude, K.K., Dinnyes, A., (2016a) The positional identity of iPSC-derived neural progenitor cells along the anterior-posterior axis is controlled in a dosage-dependent manner by bFGF and EGF. Differentiation 92, 183-194.
• Freude, K.K>., Penjwini, M., Davis, J.L., LaFerla, F.M., Blurton-Jones, M., (2011) Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J Biol Chem 286, 24264-24274.
• Kalscheuer, V.M., Freude, K., Musante, L., Jensen, L.R., Yntema, H.G., Gecz, J., Sefiani, A., Hoffmann, K., Moser, B., Haas, S., Gurok, U., Haesler, S., Aranda, B., Nshedjan, A., Tzschach, A., Hartmann, N., Roloff, T.C., Shoichet, S., Hagens, O., Tao, J., Van Bokhoven, H., Turner, G., Chelly, J., Moraine, C., Fryns, J.P., Nuber, U., Hoeltzenbein, M., Scharff, C., Scherthan, H., Lenzner, S., Hamel, B.C., Schweiger, S., Ropers, H.H., (2003) Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet 35, 313-315.