Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain

We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated 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 fibrils in the CA1 region resulted in a more faithful spreading pattern. Atlas-guided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fibril-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. [Display omitted] •Whole-brain microscopy reveals tau pathology in toto.•K18 and ePHF inoculation induce Alzheimer-like spreading of hyperphosphorylated tau.•Tau pathology follows connected brain regions.•K18-induced tau pathology is associated with rod-like and swollen microglia.•PT83 antibody lowers hyperphosphorylated tau load.