Clarity in the clouded brain: shedding light on tau pathology with whole-brain microscopic imaging
6 June 2019
UAntwerp, Stadscampus, Hof Van Liere, Tassiszaal - Prinsstraat 13 - 2000 Antwerp (route: UAntwerpen, Stadscampus
4:00 PM - 6:00 PM
Winnok De Vos, Jean-Pierre Timmermans
PhD defence Jan Detrez - Department of Biomedical Sciences
The neuropathology of Alzheimer’s disease is among other hallmarks characterised by stereotypical, progressive spreading pattern of tau pathology in the brain. It is however not known how exactly this spreading process occurs or how it correlates with cellular and functional deficits to date. The classical approach for studying cell biology in the brain, makes use of sectioned tissue, which leads to a significant loss of biological material and complicates downstream image analysis procedures.
With the advent of tissue clearing and light sheet microscopy, in toto imaging of whole organs at cellular resolution has become feasible. We have benchmarked and used this approach in a variety of transgenic mouse models and showed that targeted injection of tau fibrils in a Tau.P301L mouse model triggers a connectome-dependent spreading pattern of tau pathology that resembles the pattern observed in Alzheimer patients. We further found that fibril injection-induced tau pathology was associated with a specific microglial phenotype, typified by rod-like and swollen cell bodies. We showed that co-injection of an antibody targeting the aggregation domain of the tau could reduce the all-over pathological tau load.
One disadvantage of whole-brain microscopy is the fact that it can only be performed post-mortem and therefore does not allow assessing functional defects. To resolve this, we have performed resting state functional (rsf)MRI, enabling functional layering on volumetric histological data. However, despite overt tau pathology, no major change was observed in the resting state networks, suggesting that the accumulation of tau pathology does not affect functional connectivity per se.
In conclusion, we have established a whole-brain microscopy approach and gained insight in tau pathology development in mouse models. The combination of whole-brain microscopy with rsfMRI allowed for correlating morphological with functional information, representing a innovative imaging platform for a variety of preclinical studies, also beyond the AD domain.