Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain
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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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The general pattern of p-tau accumulation in PS19 mice matched recent reports of brain-wide p-tau accumulation in the P301L tauopathy model.
“The general pattern of p-tau accumulation matched recent reports of brain-wide p-tau accumulation in the P301L tauopathy model (Ramsden et al., 2005; Detrez et al., 2019).”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Detrez et al., 2019
In mouse models, network studies have been based on inoculation of seeds, which does not reflect a normal disease process, and is prone to experimental artifact.
“In mouse models, network studies have been based on inoculation of seeds (Sanders et al., 2014; Detrez et al., 2019), which does not reflect a normal disease process, and is prone to experimental artifact.”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Detrez et al., 2019
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Self-citationp38 activation occurs mainly in microglia in the P301S Tauopathy mouse model
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Self-citationClearing techniques for visualizing the nervous system in development, injury, and disease
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Endogenous pathology in tauopathy mice progresses via brain networksPreprint
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MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons
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Multimodal Contrast Agents for Optoacoustic Brain Imaging in Small Animals
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Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer’s disease
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Does proteopathic tau propagate trans-synaptically in the brain?
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The effects of social environment on AD-related pathology in hAPP-J20 mice and tau-P301L mice
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ClearFinder: a Python GUI for annotating cells in cleared mouse brain
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Self-citation
- Authors
- Detrez, J. R., Maurin, H., Van Kolen, K., Willems, R., Colombelli, J., Lechat, B., Roucourt, B., Van Leuven, F., Baatout, S., Larsen, P., Nuydens, R., Timmermans, J.-P., & De Vos, W. H.
- Affiliations
- University of Antwerp (BE)
- Janssen (Belgium) (BE)
- Institute for Research in Biomedicine (ES)
- KU Leuven (BE)
- Ghent University (BE)
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 127
- Pages
- 398-409
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2921462375
- Cited by
- 39
- References
- 71
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 4 · 2020: 8 · 2019: 1
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurobiology of Disease (acceptedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lirias (submittedVersion, other-oa)
- Funders
- Agentschap Innoveren en Ondernemen
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- hyperphosphorylated tau, tau seeding, regional brain vulnerability, tau propagation, Alzheimer's disease, microglia, tau fibrils, volumetric analysis
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mice, Transgenic, Neurons, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Microglia, Disease Progression, Tauopathies, Mice
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