Analyse der direkten Effekte der Interleukin-4-Signalisierung in neuralen Stamm- / Vorläuferzellen bei der Kontrolle und Alzheimer-Mäusen
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Recent findings suggest that reduced neurogenesis could be one of the underlying reasons for the exacerbated neuropathology in humans, thus restoring the neural stem cell proliferation and neurogenesis could help to circumvent some pathological aspects of Alzheimer’s disease. We identified Interleukin-4/STAT6 signaling as a neuron–glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. By using single cell sequencing in the APP/PS1dE9 mouse model of AD, we found that IL4 receptor (Il4r) is not expressed in mouse astroglia and IL4 signaling is not active in these cells. We tested whether activating IL4/STAT6 signaling would enhance cell proliferation and neurogenesis in healthy and disease conditions. Lentivirus-mediated expression of IL4R or constitutively active STAT6VT impaired the survival capacity of mouse astroglia in vivo but not in vitro. These results suggest that the adult mouse brain generates a non-permissive environment that dictates a negative effect of IL4 signaling on astroglial survival and neurogenic properties in contrast to zebrafish brains and in vitro mammalian cell cultures. Our findings that IL4R signaling in dentate gyrus (DG) of adult mouse brain impinges on the survival of DG cells implicate an evolutionary mechanism that might underlie the loss of neuroregenerative ability of the brain, which might be utilized for basic and clinical aspects for neurodegenerative diseases.
Projektbezogene Publikationen (Auswahl)
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(2018). 3D Culture Method for Alzheimer's Disease Modeling Reveals Interleukin-4 Rescues Abeta42-Induced Loss of Human Neural Stem Cell Plasticity. Dev Cell 46, 85-101 e108
Papadimitriou, C., Celikkaya, H., Cosacak, M.I., Mashkaryan, V., Bray, L., Bhattarai, P., Brandt, K., Hollak, H., Chen, X., He, S., et al.
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(2018). Is Alzheimer's Also a Stem Cell Disease? - The Zebrafish Perspective. Front Cell Dev Biol 6, 159
Kizil, C., and Bhattarai, P.
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(2019). GATA3 Promotes the Neural Progenitor State but Not Neurogenesis in 3D Traumatic Injury Model of Primary Human Cortical Astrocytes. Front Cell Neurosci 13, 23
Celikkaya, H., Cosacak, M.I., Papadimitriou, C., Popova, S., Bhattarai, P., Biswas, S.N., Siddiqui, T., Wistorf, S., Nevado-Alcalde, I., Naumann, L., et al.
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(2019). Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity. Cell Rep 27, 1307-1318 e1303
Cosacak, M.I., Bhattarai, P., Reinhardt, S., Petzold, A., Dahl, A., Zhang, Y., and Kizil, C.
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(2020). Alzheimer’s disease, neural stem cells and neurogenesis: cellular phase at single-cell level. Neural Reg Res 15, 824-827
Cosacak, M.I., Bhattarai, P., and Kizil, C.
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(2020). Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain. PLoS Biol 18, e3000585
Bhattarai, P., Cosacak, M.I., Mashkaryan, V., Demir, S., Popova, S., Govindarajan, N., Brandt, K., Zhang, Y., Chang, W., Ampatzis, K., et al.
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(2020). Protocol for Dissection and Dissociation of Zebrafish Telencephalon for Single-Cell Sequencing. STAR Protoc 1, 100042
Cosacak, M.I., Bhattarai, P., and Kizil, C.
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(2020). Radial glia in the zebrafish brain: Functional, structural, and physiological comparison with the mammalian glia. Glia
Jurisch-Yaksi, N., Yaksi, E., and Kizil, C.
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(2020). Type 1 Interleukin-4 signaling obliterates mouse astroglia in vivo but not in vitro. Frontiers in Cell and Developmental Biology 8, 114
Mashkaryan, V., Siddiqui, T., Popova, S., Cosacak, M.I., Bhattarai, P., Brandt, K., Govindarajan, N., Petzold, A., Reinhardt, S., Dahl, A., et al.
