Translational Neurodegeneration

Research Focus

We use induced pluripotent stem cells, iPSCs (Fig. 1A, B), for modelling and understanding human brain diseases as well as for regenerative therapies with a focus on Alzheimer’s Disease (AD) and stroke, respectively.

The APOE4 allele is the most important genetic risk factor for AD, while the presence of APOE3 is risk-neutral and APOE2 is protective. As the main lipid carrier, APOE has a prominent role in the bioenergetic homeostasis of the brain. However, the role of different APOE isoforms for the metabolic state of human brain cells is still unknown. Using APOE isogenic iPSCs that differ in their APOE allele, we aim to uncover the underlying mechanisms of APOE4-mediated metabolic dysfunctions in differentiated human cortical neurons (iN cells; Fig 1C, D) and astrocytes (iAstrocytes; Fig. 1E, F). Thereby, we contribute to the mechanistic understanding of AD pathogenesis and get novel insights into the detrimental role of APOE4 and the protective effects of APOE2.

Ischemic stroke causes a permanent disability to five million people each year. This is largely due to the lack of effective medical treatments that promote long-term recovery. Therefore, we are developing a next-generation regenerative therapy for stroke based on xeno-free iPSC-derived neural progenitor cells (NPCs; Fig. 1G, H). These are transplanted into mice that received a photothrombotic stroke (Fig. 1I) and tracked longitudinally using in vivo bioluminescence imaging (Fig. 1 J, K). After 5 weeks, grafted NPCs mostly differentiate into neurons, while no signs of remaining pluripotent cells are visible (Fig. 1L). We further work on improving applicability, efficacy and safety to advance cell therapy for brain injuries towards potential clinical application. This project is carried out in close collaboration with USC researcher and IREM guest scientist Prof. Ruslan Rust.

A: Phase contrast microscopy of an iPSC colony. B: iPCS colony stained for pluripotency markers Nanog and Tra-1-60. C, D: Induced neurons (iN cells) from iPSCs at DIV21 are positive for the neuronal markers tau and Map2 and display PSD-95-positive postsynaptic as well as synapsin-positive presynaptic punctae. E, F: iAstrocytes express astrocytic markers S100β, GJA1 (Connexin 43) and GFAP. G, H: Neural progenitor cells (NPCs), derived from iPSCs, express typical marker proteins Pax6, Sox1, Nestin but not pluripotency marker Oct4. I: Schematic representation of the photothrombotic stroke mouse model. J, K: Transduction of NPCs with a bioluminescent reporter (J) allows longitudinal tracking of grafted cells using in vivo bioluminescence imaging (K). L: Histological stainings of grafted NPCs at 35d post transplantation.
Images are taken from de Leeuw at al., 2022, Stem Cell Reports; Rust et al., 2022, Journal of Translational Medicine; de Leeuw and Tackenberg, 2019, Translational Neurodegeneration; Birnbaum et al., 2018, Stem Cell Research.

Funding

Swiss Commission for Technology and Innovation (Innosuisse); Swiss National Science Foundation (SNSF); Dr. Wilhelm Hurka Foundation; Hartmann-Müller Foundation; Vontobel Foundation; Novartis Foundation for Medical-Biological Research; Swiss 3R Competence Center; University of Zurich; Olga Mayenfisch Foundation; Neuroscience Center Zurich; Betty & David Koetser Foundation for Brain Research; German Research Foundation