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

We are currently working with 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 modeling of both FTD and AD.

We have recently received funding from the Novo Nordisk Foundation (GliAD) to investigate the role of specific single nucleotide polymorphisms (SNPs) related to the innate immune system in sporadic AD.

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).

Research Funding

Selected Publications

• 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.