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                                          3. JäkelLab

                                          Jäkel-Lab – Oligodendrocyte Pathology

                                          • Research Focus
                                          • PI
                                          • Publications
                                          Jäkel Lab Visual

                                          We are interested in the role of oligodendrocytes – the myelin forming cells in the central nervous system – in Alzheimer’s disease. For decades, the pathology in Alzheimer’s has been considered purely neuronal, however, recent advances have clearly demonstrated glial involvement, initiating a shift in scientific focus. Oligodendrocytes have been shown to be the first cell type to transcriptionally change in the earliest stages of the disease, while the functional importance of these changes still remains unknown. With an expertise in human oligodendrocyte biology, our lab aims to describe changes in the cellular distribution of oligodendrocytes in the human brain and to unravel how their functional changes contribute to the pathogenesis of Alzheimer’s disease.

                                          Our work is based on the observation that developmental cortical myelination does not happen all at once and late myelinated regions are affected earlier by Alzheimer’s disease than early myelinated ones. My previous work revealed oligodendrocytes in the human brain are heterogeneous, representing different states that might exhibit different functions. In the context of Alzheimer’s disease, this could in turn influence the vulnerability of neurons to degenerate within different brain areas. Hence, by understanding the distribution and the function of different oligodendrocyte states we aim to explain why some brain regions are more affected by Alzheimer’s than others.

                                          Our research focuses on the human disease itself rather than mimicking it in animal models and is thus highly translational. We use a combination of cutting-edge transcriptomic approaches such as single-nuclei RNA-sequencing on post-mortem human brain tissue, as well as two and three-dimensional human stem cell-derived oligodendrocyte cultures as model systems in which we recreate and characterize the functional oligodendrocyte cell states.

                                          Contact: Dr. Sarah Jäkel
                                          Tel: +49-89-4400-46238
                                          E-Mail: sarah.jaekel@med.uni-muenchen.de

                                          Sarah Jäkel

                                          Dr. Sarah Jäkel

                                          Motivation:

                                          I am fascinated by the biology of oligodendrocytes: they are small cells producing large amounts of membrane, which can be >100 times the surface of their cell body and wrap it in a highly organized way around several axons. Most of this happens after birth, when the major parts of the brain, including neurons, are already fully developed. Oligodendrocytes and myelin are probably the most plastic parts in our brain and keep changing until the end of our lifetime. They are indispensable for a fast saltatory nerve conduction and thus making our body work as it should, but also for providing metabolic support to the otherwise insulated axons to keep them healthy.

                                          It is not surprising that malfunctioning oligodendrocytes are involved in numerous neurological disorders including neurodegenerative diseases, in which oligodendrocytes have long been neglected. I studied oligodendrocytes in mouse models during my PhD at the department of Physiological Genomics at the LMU, but then I decided to move to translational neuroscience studying diseases directly on human tissue. Although disease models are of highest importance in science, the accompanying use of human tissue is essential and complementary to understanding human disease pathology. I then studied oligodendrocytes in Multiple Sclerosis in my postdoctoral time at the Centre for Regenerative Medicine at the University of Edinburgh. Studying oligodendrocytes in neurodegenerative diseases is exciting for me, because almost nothing is known about their involvement in the disease, leaving a lot to explore. Moreover, this research topic is of high importance from a clinical perspective. Due to their highly plastic nature, oligodendrocytes are more tractable to therapy than for examples neurons, thus opening completely new possibilities for drug development in Alzheimer’s disease and possibly other forms of dementia.

                                          I also enjoy being engaged in science communication activities for the general public including children. In my eyes, it is important that non-scientists get a better and more realistic picture of our work and that all children have an equal chance to understand science.

                                          Scientific Career:

                                          2021 onwards: Emmy-Noether junior group leader, Institute for Stroke and Dementia Research, LMU Munich.

                                          2016-2020: Marie-Sklodowska Curie Postdoctoral Research Fellow, Centre for Regenerative Medicine, University of Edinburgh

                                          2012-2016: PhD, Graduate School of Systemic Neuroscience and Department of Physiological Genomics, LMU Munich

                                          2009-2011: MSc, Molecular Biotechnology, TU Munich


                                          2020

                                          Jäkel S, Williams A. What Have Advances in Transcriptomic Technologies Taught us About Human White Matter Pathologies? Front Cell Neurosci. 2020 Aug 4;14:238. 

                                          Macchi M, Magalon K, Zimmer C, Peeva E, El Waly B, Brousse B, Jaekel S, Grobe K, Kiefer F, Williams A, Cayre M, Durbec P. Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulfate production. Elife. 2020 Jun 9;9:e51735. 

                                          2019

                                          Jäkel S, Agirre E, Mendanha Falcão A, van Bruggen D, Lee KW, Knuesel I, Malhotra D, Ffrench-Constant C, Williams A, Castelo-Branco G. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. 2019 Feb;566(7745):543-547. 

                                          2018

                                          Falcão AM, van Bruggen D, Marques S, Meijer M, Jäkel S, Agirre E, Samudyata, Floriddia EM, Vanichkina DP, Ffrench-Constant C, Williams A, Guerreiro-Cacais AO, Castelo-Branco G. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat Med. 2018 Dec;24(12):1837-1844. 

                                          2017

                                          Jäkel S, Dimou L. Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Front Cell Neurosci. 2017 Feb 13;11:24. 

                                          Fard MK, van der Meer F, Sánchez P, Cantuti-Castelvetri L, Mandad S, Jäkel S, Fornasiero EF, Schmitt S, Ehrlich M, Starost L, Kuhlmann T, Sergiou C, Schultz V, Wrzos C, Brück W, Urlaub H, Dimou L, Stadelmann C, Simons M. BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions. Sci Transl Med. 2017 Dec 6;9(419):eaam7816. 

                                          2016

                                          Schneider S, Gruart A, Grade S, Zhang Y, Kröger S, Kirchhoff F, Eichele G, Delgado García JM, Dimou L. Decrease in newly generated oligodendrocytes leads to motor dysfunctions and changed myelin structures that can be rescued by transplanted cells. Glia. 2016 Dec;64(12):2201-2218. 

                                          Djogo T, Robins SC, Schneider S, Kryzskaya D, Liu X, Mingay A, Gillon CJ, Kim JH, Storch KF, Boehm U, Bourque CW, Stroh T, Dimou L, Kokoeva MV. Adult NG2-Glia Are Required for Median Eminence-Mediated Leptin Sensing and Body Weight Control. Cell Metab. 2016 May 10;23(5):797-810. 

                                          Viganò F, Schneider S, Cimino M, Bonfanti E, Gelosa P, Sironi L, Abbracchio MP, Dimou L. GPR17 expressing NG2-Glia: Oligodendrocyte progenitors serving as a reserve pool after injury. Glia. 2016 Feb;64(2):287-99. 

                                          2015

                                          Sirko S, Irmler M, Gascón S, Bek S, Schneider S, Dimou L, Obermann J, De Souza Paiva D, Poirier F, Beckers J, Hauck SM, Barde YA, Götz M. Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. Glia. 2015 Dec;63(12):2340-61. 

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                                          Director: Prof. Dr. med. Martin Dichgans

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