Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain

Research output: Contribution to journalArticle

Authors

  • Jan R. Detrez
  • Hervé Maurin
  • Kristof Van Kolen
  • Roland Willems
  • Julien Colombelli
  • Benoit Lechat
  • Bart Roucourt
  • Fred Van Leuven
  • Sarah Baatout
  • Peter Larsen
  • Rony Nuydens
  • Jean-Pierre Timmermans
  • Winnok H. De Vos

Institutes & Expert groups

  • UA - Universiteit Antwerpen
  • Janssen Research and Development - Department of Neuroscience
  • IRB - Institute for Research in Biomedicine - The Barcelona Institute of Science and Technology
  • KUL - Katholieke Universiteit Leuven
  • reMYND NV - Bio-Incubator Leuven
  • UGent - Universiteit Gent

Documents & links

Abstract

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. Atlasguided 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

Details

Original languageEnglish
Pages (from-to)398-409
Number of pages12
JournalNeurobiology of Disease
Volume127
DOIs
Publication statusPublished - 14 Mar 2019

Keywords

  • Hyperphosphorylated tau, Tau, Alzheimer's disease, Tau.P301L, Whole brain imaging, Light-sheet microscopy, Tissue clearing, Microglia

ID: 5034883