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Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain

  • Detrez, Jan R
  • Maurin, Hervé
  • Van Kolen, Kristof
  • Willems, Roland
  • Colombelli, Julien
  • Lechat, Benoit
  • Roucourt, Bart
  • Van Leuven, Fred
  • Baatout, Sarah
  • Larsen, Peter
  • Nuydens, Rony
  • Timmermans, Jean-Pierre
  • De Vos, Winnok
Publication Date
Jan 01, 2019
Ghent University Institutional Archive
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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.

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