Comparative In Vitro and In Vivo Quantifications of Pathologic Tau Deposits and Their Association with Neurodegeneration in Tauopathy Mouse Models
Open accessAbstract
Fibrillary tau aggregates in Alzheimer disease and allied neurodegenerative disorders have been visualized in vivo by PET, whereas mechanistic links between PET-detectable tau deposits and neurotoxicity remain elusive. Here, we took advantage of transgenic mouse models of tauopathies to evaluate associations between PET and postmortem measures of tau probe binding and their relation to neuronal loss. Methods: PET with a tau probe, 11C-PBB3 (2-((1E,3E)-4-(6-(11C-methylamino)pyridine-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol), and volumetric MRI were performed for transgenic rTg4510 mice and nontransgenic mice. Binding of 11C-PBB3 and its blockade by another tau binding compound, AV-1451 (-(6-fluoropyridine-3-yl)-5H-pyrido[4,3-b]indole), in homogenized brains of tauopathy patients and rTg4510 and PS19 mice were quantified, and 11C-PBB3–positive and phosphorylated tau lesions in sectioned brains of these mice were assessed. Results: In vivo 11C-PBB3 binding to the rTg4510 neocortex/hippocampus was increased relative to controls and correlated with local atrophy. In vitro 11C-PBB3 binding in the neocortex/hippocampus also correlated well with in vivo radioligand binding and regional atrophy in the same individual rTg4510 mice. By contrast, in vitro 11C-PBB3 binding was elevated in the brain stem but not hippocampus of PS19 mice, despite a pronounced loss of neurons in the hippocampus rather than brain stem. Finally, 11C-PBB3 and AV-1451 showed similar binding properties between mouse models and tauopathy patients. Conclusion: The present findings support the distinct utilities of 11C-PBB3 PET and MRI in rTg4510 and PS19 mice for quantitatively pursuing mechanisms connecting PET-detectable and PET-undetectable tau aggregations to neuronal death, which recapitulate 2 different modes of tau-provoked neurotoxicity.
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Effects of tauopathy on DTI metrics in grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies.
“Effects of tauopathy on DTI metrics in the grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies [17,18,23,25,28,29,33,38,57].”
From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [28]
The paper’s introductory text describes disruption of the axonal framework in tau disease, and its Abstract and Discussion report neuronal loss in tauopathy mouse models. It does not assess DTI metrics or myelin injury. The Discussion mentions astrogliosis as a possible source of PET-tracer signal, not as a demonstrated contributor to the claimed DTI effects. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHistological studies have demonstrated deposition of NFTs pathology, in particular in the cortex and hippocampus, and marked atrophy of these areas.
“Histological studies have demonstrated deposition of NFTs pathology, in particular, in the cortex (CRX) and hippocampus and marked atrophy of these areas [27][28][29][30][31][32].”
From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [28]
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Massalimova, A., Ni, R., Nitsch, R. M., Reisert, M., von Elverfeldt, D., & Klohs, J. (2020) · Neurodegenerative Diseases · doi:10.1159/000515754 · Cited by 28 · see citing works
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- Authors
- Ni, R., Ji, B., Ono, M., Sahara, N., Zhang, M.-R., Aoki, I., Nordberg, A., Suhara, T., & Higuchi, M.
- Affiliations
- Karolinska University Hospital (SE)
- National Institutes for Quantum Science and Technology (JP)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2018-02-01
- Volume
- 59
- Issue
- 6
- Pages
- 960-966
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- OpenAlex
- W2785763878
- Cited by
- 72
- References
- 8
- Citations by year
- 2025: 7 · 2024: 9 · 2023: 9 · 2022: 18 · 2021: 8 · 2020: 13 · 2019: 6 · 2018: 2
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- University of Pennsylvania
- University of Florida
- Japan Society for the Promotion of Science (16K19872, 15K09979, 15K06793, 16H05324)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tauopathy, [11C]PBB3, tau PET imaging, rTg4510 mice, PS19 mice, neurodegeneration, neuronal loss, brain atrophy, phosphorylated tau, transgenic mouse model, Alzheimer's disease, hippocampus, brainstem
- MeSH terms
- Aminopyridines, Animals, Atrophy, Brain, Carbolines, Disease Models, Animal, Magnetic Resonance Imaging, tau Proteins, Tauopathies, Positron-Emission Tomography, Mice, Benzothiazoles, Multimodal Imaging
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