Whole brain imaging of disease models allowed the assessment of hyperphosphorylated tau deposition patterns, allowing the development of models that reflected the clinical situation
3D atlas mapping and regional analysis revealed that stereotactic injection with synthetic or patient-derived tau fbrils induced a tau pathology pattern that resembled that of AD patients, and which was associated with a specific microglial subpopulation. By co-administration of a microtubulebinding domain targeting antibody, we also showed its potential for therapeutic intervention studies
“Collaboration across multiple sites is essential to bring together expertise in disease models, therapies and measurement techniques. Without this framework, world-leading science cannot be carried out”
Sites engaged: KUL, Ghent, Antwerp
We have exploited whole brain microscopy to map the progressive deposition of hyper-phosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Injection of synthetic or patient-derived tau fbrils in the CA1 region resulted in a more faithful spreading pattern. Atlasguided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fbril-injected brains, we also detected a persistent subpopulation of rod-like and swollen microglia. Furthermore, we showed that the hyperphosphorylated tau load could be reduced by intracranial co-administration of, and to a lesser extent, by repeated systemic dosing with an antibody targeting the microtubule-binding domain of tau. Thus, the combination of targeted seeding and in toto staging of tau pathology allowed assessing regional vulnerability in a comprehensive manner, and holds potential as a preclinical drug validation tool.