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Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain

Jan R Detrez, Hervé Maurin, Kristof Van Kolen, Roland Willems, Julien Colombelli, Benoit Lechat, Bart Roucourt, Fred Van Leuven, Sarah Baatout (UGent) , Peter Larsen, et al.
(2019) NEUROBIOLOGY OF DISEASE. 127. p.398-409
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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. 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.
Keywords
Hyperphosphorylated tau, Tau, Alzheimer's disease, Tau.P301L, Whole brain imaging, Light-sheet microscopy, Tissue clearing, Microglia, ALZHEIMERS-DISEASE, ANTIBODY UPTAKE, AMYLOID-BETA, PATHOLOGY, PROTEIN, TAUOPATHY, MODEL, TRANSMISSION, FILAMENTS, FIBRILS

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MLA
Detrez, Jan R., et al. “Regional Vulnerability and Spreading of Hyperphosphorylated Tau in Seeded Mouse Brain.” NEUROBIOLOGY OF DISEASE, vol. 127, 2019, pp. 398–409, doi:10.1016/j.nbd.2019.03.010.
APA
Detrez, J. R., Maurin, H., Van Kolen, K., Willems, R., Colombelli, J., Lechat, B., … De Vos, W. (2019). Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain. NEUROBIOLOGY OF DISEASE, 127, 398–409. https://doi.org/10.1016/j.nbd.2019.03.010
Chicago author-date
Detrez, Jan R, Hervé Maurin, Kristof Van Kolen, Roland Willems, Julien Colombelli, Benoit Lechat, Bart Roucourt, et al. 2019. “Regional Vulnerability and Spreading of Hyperphosphorylated Tau in Seeded Mouse Brain.” NEUROBIOLOGY OF DISEASE 127: 398–409. https://doi.org/10.1016/j.nbd.2019.03.010.
Chicago author-date (all authors)
Detrez, Jan R, 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, and Winnok De Vos. 2019. “Regional Vulnerability and Spreading of Hyperphosphorylated Tau in Seeded Mouse Brain.” NEUROBIOLOGY OF DISEASE 127: 398–409. doi:10.1016/j.nbd.2019.03.010.
Vancouver
1.
Detrez JR, Maurin H, Van Kolen K, Willems R, Colombelli J, Lechat B, et al. Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain. NEUROBIOLOGY OF DISEASE. 2019;127:398–409.
IEEE
[1]
J. R. Detrez et al., “Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain,” NEUROBIOLOGY OF DISEASE, vol. 127, pp. 398–409, 2019.
@article{8612690,
  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. 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.}},
  author       = {{Detrez, Jan R and Maurin, Hervé and Van Kolen, Kristof and Willems, Roland and Colombelli, Julien and Lechat, Benoit and Roucourt, Bart and Van Leuven, Fred and Baatout, Sarah and Larsen, Peter and Nuydens, Rony and Timmermans, Jean-Pierre and De Vos, Winnok}},
  issn         = {{0969-9961}},
  journal      = {{NEUROBIOLOGY OF DISEASE}},
  keywords     = {{Hyperphosphorylated tau,Tau,Alzheimer's disease,Tau.P301L,Whole brain imaging,Light-sheet microscopy,Tissue clearing,Microglia,ALZHEIMERS-DISEASE,ANTIBODY UPTAKE,AMYLOID-BETA,PATHOLOGY,PROTEIN,TAUOPATHY,MODEL,TRANSMISSION,FILAMENTS,FIBRILS}},
  language     = {{eng}},
  pages        = {{398--409}},
  title        = {{Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain}},
  url          = {{http://dx.doi.org/10.1016/j.nbd.2019.03.010}},
  volume       = {{127}},
  year         = {{2019}},
}
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