Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning
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Abstract
Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods: Transgenic P301S ( n = 33) and wild-type ( n = 18) female mice were imaged by 18 F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18 F-fluordesoxyglucose ( 18 F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3–6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models. Results: TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11–23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3–6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3–6.7 months. Conclusions: Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.
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The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards deficits in the MWM test from 5 or 6.5 months, while others report initial deficits in spatial memory at 10 or 12 months of age.
“The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards the development of deficits in the MWM test from a relatively young age of 5 [28] or 6.5 months [41], while others report initial deficits in spatial memory at 10 [42] or even 12 months of age [29], respectively.”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [41]
The Results (no page available) report Morris water maze deficits in P301S mice at 6.3 months, supporting the early-deficit part of the cited clause. However, Animals and study design identifies these mice as a human P301S tau line driven by the murine thy1 promoter; our copy does not identify them as the PS19 line. The test age is also 6.3, rather than 6.5, months. (LLM, conf=0.86)
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- Authors
- Eckenweber, F., Medina-Luque, J., Blume, T., Sacher, C., Biechele, G., Wind, K., Deussing, M., Briel, N., Lindner, S., Boening, G., von Ungern-Sternberg, B., Unterrainer, M., Albert, N. L., Zwergal, A., Levin, J., Bartenstein, P., Cumming, P., Rominger, A., Höglinger, G. U., Herms, J., & Brendel, M.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Deutsches Schwindel- und Gleichgewichtszentrum (DE)
- Munich Cluster for Systems Neurology (DE)
- Queensland University of Technology (AU)
- University Hospital of Bern (CH)
- Corresponding author
- Brendel, Matthias
- ORCID
- Venue
- Journal of Neuroinflammation
- Published
- 2020-07-13
- Volume
- 17
- Issue
- 1
- Pages
- 208-208
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC7358201
- OpenAlex
- W3041601263
- Cited by
- 32
- References
- 34
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 8 · 2020: 2
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (BR4580/1-1, RO5194/1-1, EXC 2145 SyNergy – ID 390857198)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- P301S tau transgenic mice, translocator protein (TSPO), microglial activation, neuroinflammation, tau accumulation, neurofibrillary tangles, spatial learning, brain glucose metabolism, longitudinal imaging, hippocampus, brainstem
- MeSH terms
- Animals, Brain, Female, Forecasting, Mice, Transgenic, Gene Expression, Neurofibrillary Tangles, tau Proteins, Receptors, GABA, Mice, Spatial Learning
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