Dataset Information

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

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 ?PET) 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 ?PET 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) ?PET, and AT8 tau immunohistochemistry at 6.3-6.7?months. Terminal microglial immunohistochemistry served for validation of TSPO ?PET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-? 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-? 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 ?PET indicates a delayed time course when compared to amyloid-? mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-? mouse models. The contribution of microglial response to pathology accompanying amyloid-? and tau over-expression merits further investigation.

SUBMITTER: Eckenweber F

PROVIDER: S-EPMC7358201 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Eckenweber Florian F Medina-Luque Jose J Blume Tanja T Sacher Christian C Biechele Gloria G Wind Karin K Deussing Maximilian M Briel Nils N Lindner Simon S Boening Guido G von Ungern-Sternberg Barbara B Unterrainer Marcus M Albert Nathalie L NL Zwergal Andreas A Levin Johannes J Bartenstein Peter P Cumming Paul P Rominger Axel A Höglinger Günter U GU Herms Jochen J Brendel Matthias M

Journal of neuroinflammation 20200713 1

<h4>Background</h4>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 asses ...[more]

PMID: 32660586

Similar Datasets

Project description:Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-β-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P-T-; n = 30), tau-discordant (i.e. A+P+T-; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in tau-PET was faster in the A+P+T- group than in the control and A+P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T- group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest updating the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).

Project description:BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

Project description:BackgroundNeuronal accumulation of misfolded microtubule-associated protein tau is a hallmark of neuropathology in Alzheimer's disease, frontotemporal dementia, and other tauopathies, and has been a therapeutic target. Microglia can spread tau pathology by secreting tau-containing exosomes, although the specific molecular target is yet to be identified for the therapeutic intervention. P2X purinoceptor 7 (P2RX7) is an ATP-gated cation channel, enriched in microglia and triggers exosome secretion. The purpose of the study is to examine the therapeutic effect of an orally applicable, CNS-penetrant P2RX7 specific inhibitor on the early disease stage of a tauopathy mouse model.MethodsThree-months-old P301S tau mice were treated with P2RX7-specific inhibitor GSK1482160 or vehicle for 30 days, followed by behavioral, biochemical and immunohistochemical assessment. GSK1482160 was also tested for exosome secretion from primary cultured murine astrocytes, neurons and microglia in vitro.ResultsOral administration of GSK1482160 significantly reduced accumulation of MC1+ and Alz50+ misfolded tau in hippocampal regions, which was accompanied with reduced accumulation of Tsg101, an exosome marker, in hippocampal neurons. Proximity ligation assay demonstrated complex formation of Alz50+ tau and Tsg101 in hippocampal neurons, which was reduced by GSK1482160. On the other hand, GSK1482160 had no effect on microglial ramification or CD68 expression, which was significantly enhanced in P301S mice, or pro/anti-inflammatory cytokine gene expression. Strikingly, GSK1482160-treated P301S mice show significantly improved working and contextual memory as determined by Y-maze and fear conditioning tests. GSK1482160 also significantly increased accumulation of Tsg101 and CD81 in microglia in vivo, suggesting its suppression of P2RX7-induced exosome secretion from microglia. This effect was confirmed in vitro, as ATP-induced secretion of tau-containing exosome was significantly suppressed by GSK1482160 treatment from primary murine microglia, but not from neurons or astrocytes.DiscussionThe oral administration of P2RX7 inhibition mitigates disease phenotypes in P301S mice, likely by suppressing release of microglial exosomes. P2RX7 could be a novel therapeutic target for the early stage tauopathy development.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets