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Title
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Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain
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Author
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Abstract
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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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Language
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English
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Source (journal)
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Neurobiology of disease. - San Diego, Calif.
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Publication
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San Diego, Calif.
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2019
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ISSN
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0969-9961
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DOI
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10.1016/J.NBD.2019.03.010
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Volume/pages
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127
(2019)
, p. 398-409
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ISI
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000472990100034
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Pubmed ID
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30878534
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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