Journal
NEUROBIOLOGY OF DISEASE
Volume 127, Issue -, Pages 398-409Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.03.010
Keywords
Hyperphosphorylated tau; Tau; Alzheimer's disease; Tau.P301L; Whole brain imaging; Light-sheet microscopy; Tissue clearing; Microglia
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Funding
- Baekeland Grant of Flanders Innovation and Entrepreneurship (VLAIO) [IWT140775]
- Rotary Campaign 'Hope in Head' 2017
- SAO [2017.0006]
- MRC [G0400074] Funding Source: UKRI
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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 tote 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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