Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning.

DOI
Publisher DOI
PubMed ID
32660586
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 18F-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, 18F-fluordesoxyglucose (18F-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.
Date Issued
2020-07-13
Publication Type
Article
Subject(s)
Subjects
Glucose metabolism Microglia P301S PET Spatial learning TSPO Tau
Language(s)
en
Author(s)
Eckenweber, Florian
Medina-Luque, Jose
Blume, Tanja
Sacher, Christian
Biechele, Gloria
Wind, Karin
Deussing, Maximilian
Briel, Nils
Lindner, Simon
Boening, Guido
von Ungern-Sternberg, Barbara
Unterrainer, Marcus
Albert, Nathalie L
Zwergal, Andreas
Levin, Johannes
Bartenstein, Peter
Höglinger, Günter U
Herms, Jochen
Brendel, Matthias
Additional Credits
Journal
Journal of neuroinflammation
Publisher
BioMed Central
ISSN
1742-2094
Access(Rights)
Unknown
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