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
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Sites engaged: KUL, Ghent, Antwerp
Abstract
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.