Systems microscopy sheds light on neurodegeneration across scales

Session

Poster Session

Authors

Marlies Verschuuren (1, 2, 3), Sarah De Beuckeleer (2, 3), Tim Van De Looverbosch (2, 3), Peter Verstraelen (2, 3), Sofie Thys (1, 2, 3), Jean-Pierre Timmermans (1, 2, 3), Isabel Pintelon (1, 2, 3), Winnok De Vos (1, 2, 3)

Affiliations

1. Antwerp Centre for Advanced Microscopy, University of Antwerp, Antwerp
2. Laboratory of Cell Biology & Histology, University of Antwerp, Department of Veterinary Sciences, Antwerp
3. µNEURO Research Excellence Centre, University of Antwerp, Antwerp

Keywords

Systems microscopy, Electron Microscopy, High-throughput screening, Light sheet microscopy, Neurodegeneration

Abstract text

The Antwerp Centre for Advanced Microscopy (ACAM) (www.acam-uantwerpen.be) develops workflows for data-driven, systems microscopy, based on a diversity of imaging technologies including electron microscopy, high-throughput screening, ultra-fast live cell imaging and light sheet microscopy. An illustration of how we integrate modalities across scales is its application to the field of neurodegeneration. At the ultrastructural level, we have used transmission electron microscopy to identify defects in the myelin morphology,  e.g. by measuring the amelioration of the dysmyelination in compound treated organoid models for peripheral neuropathy¹. At the cellular level, we have established a quantitative image-based assay for profiling morphofunctional connectivity in primary and iPSC-derived neuronal cultures as a sensitive and integrated readout for their maturation or drug response^2-5. We have generalized our high-content pipeline to identify cell types and cell states in more complex, physiologically relevant biological specimens such as mixed neuronal cultures⁶, and are currently exploring its applicability to cerebral organoids. Given the opacity of the organoids, we build on an in toto microscopy approach that we have optimized for whole mouse brain. We have used this approach to monitor the spatiotemporal spreading of tau pathology throughout the brain of a seeded transgenic mouse model⁷ and to characterize the impact of microglial depletion⁸. Thus, together our imaging expertise allows quantitative investigation of defects in neurodegenerative disorders across scales. ACAM is accessible to European users via Flanders Bioimaging, official Euro-BioImaging member. 

Funding: Universiteit Antwerpen, Grant/Award Numbers: BOF IMARK, IOF FFI210242, µNEURO Research Foundation Flanders, Grant/Award Numbers: FWO 1152918N, FWO G005819N, FWO I003420N, FWO I000321N 

References

1. Van Lent, J., Vendredy, L., Adriaenssens, E., Da Silva Authier, T., Asselbergh, B., Kaji, M., Weckhuysen, S., Van Den Bosch, L., Baets, J. and Timmerman V. (2023). Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A. Brain. 146:2885-2896. 10.1093/brain/awac475. 

2. Verstraelen, P., Garcia-Diaz Barriga, G., Verschuuren, M., Asselbergh, B., Nuydens, R., Larsen, P.H., Timmermans, J.P., and de Vos, W.H. (2020). Systematic Quantification of Synapses in Primary Neuronal Culture. iScience 23, 101542. 10.1016/j.isci.2020.101542.

3. Verschuuren, M., Verstraelen, P., Garcia-Diaz Barriga, G., Cilissen, I., Coninx, E., Verslegers, M., Larsen, P.H., Nuydens, R., and de Vos, W.H. (2019). High-throughput microscopy exposes a pharmacological window in which dual leucine zipper kinase inhibition preserves neuronal network connectivity. Acta Neuropathol Commun 7, 93. 10.1186/s40478-019-0741-3.

4. Kuijlaars, J., Oyelami, T., Diels, A., Rohrbacher, J., Versweyveld, S., Meneghello, G., Tuefferd, M., Verstraelen, P., Detrez, J.R., Verschuuren, M., et al. (2016). Sustained synchronized neuronal network activity in a human astrocyte co-culture system. Sci Rep 6, 36529. 10.1038/srep36529.

5. Verstraelen, P., Verschuuren, M., and De Vos W.H. (2024). Integrated quantification of morpho-functional connectivity in neuronal cultures. STAR Protocols, accepted

6. De Beuckeleer, S., Van de Looverbosch, T., Van Den Daele, J., Ponsaerts, S., and De Vos, W.H. (2024). Unbiased identification of cell identity in dense mixed neural cultures. bioRxiv 2024.01.06.574474; https://doi.org/10.1101/2024.01.06.574474. 

7. Detrez, J.R., Ben-Nejma, I.R.H., van Kolen, K., van Dam, D., de Deyn, P.P., Fransen, E., Verhoye, M., Timmermans, J.-P., Nuydens, R., van der Linden, A., et al. (2020). Progressive tau aggregation does not alter functional brain network connectivity in seeded hTau.P301L mice. Neurobiol Dis 143, 105011. 10.1016/j.nbd.2020.105011.

8. Gruel, R., Bijnens, B., Van Den Daele, J., Thys, S., Willems, R., Wuyts, D., Van Dam, D., Verstraelen, P., Verboven, R., Roels, J., VanDamme, N., Manusco, R., Pita-Almenar, J.D., De Vos, W.H. (2024). S100A8-enriched microglia populate the brain of tau-seeded. bioRxiv 2023.11.10.566543; doi: https://doi.org/10.1101/2023.11.10.566543