Jäkel-Lab – Oligodendrocyte Pathology
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
Dr. Sarah Jäkel
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.
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
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.