In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510

Ishikawa, Ai; Takao, Masaki; Maeda, Jun; Minamihisamatsu, Takeharu; Shimojo, Masafumi; Takuwa, Hiroyuki; Ono, Masahiro; Ni, Ruiqing; Hirano, Shigeki; Kuwabara, Satoshi; Ji, Bin; Zhang, Ming‐Rong; Aoki, Ichio; Suhara, Tetsuya; Higuchi, Makoto; Sahara, Naruhiko

doi:10.3233/jad-170509

Cited by 64 publications

(78 citation statements)

References 55 publications

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“…From the 1.5 h dynamic scans, we found that the radiotracer uptakes were mainly located in the brain regions such as the cortex, hippocampus, and striatum, which is comparable with previous findings [23], further confirming the tau-specific binding ability of 18 F-PM-PBB3. The steady-state for each brain region from the TAC was found roughly 40 min after the tracer injection, which also matches the results of studies using C-11 labeled PBB3 [17,31]. The tracer kinetic distribution on the rTg4510 mouse brain regions is slower than 18 F-THK523, which reached the plateau roughly 20-30 min post tracer injection [11].…”

Section: Discussionsupporting

confidence: 81%

“…Afterward, another advanced radioligand, 18 F-THK5351, was developed with much lower white matter binding and higher binding specificity only focusing on the abnormal tau-associated regions [14,15]. However, the dominant binding was delineated from 18 F-THK5351 in the brain regions such as the basal ganglia, thalamus, and brainstem and this tracer's off-target binding to monoamine oxidase-B (MAO-B) has been verified [16,17]. Like 18 F-THK5351, 18 F-Flotaucipir has also demonstrated superior binding properties specific to tau proteins [18][19][20]; however, this tracer also has the off-targeting issue, and it has been further confirmed that this non-specific binding could be derived from monoamine oxidase-A (MAO-A) or MAO-B [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

et al. 2020

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Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer’s disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model of tauopathy. Dynamic PET scans were collected in groups of rTg4510 transgenic mice at 2–11 months of age. Associations between distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) with cerebellum reference were used to determine the optimal scanning time and uptake pattern for each age. Immunohistochemistry staining of neurofibrillary tangles and autoradiography study was performed for ex vivo validation. An SUVR 40–70 min was most consistently correlated with DVR and was used in further analyses. Significant increased 18F-PM-PBB3 uptake in the brain cortex was found in six-month-old mice (+28.9%, p < 0.05), and increased further in the nine-month-old group (+38.8%, p < 0.01). The trend of increased SUVR value remained evident in the hippocampus and striatum regions except for cortex where uptake becomes slightly reduced in 11-month-old animals (+37.3%, p < 0.05). Radioactivity distributions from autoradiography correlate well to the presence of human tau (HT7 antibody) and hyperphosphorylated tau (antibody AT8) from the immunohistochemistry study of the adjacent brain sections. These findings supported that the 40–70 min 18F-PM-PBB3 PET scan with SUVR measurement can detect significantly increased tau deposits in a living rTg4510 transgenic mouse models as early as six-months-old. The result exhibited promising dynamic imaging capability of this novel tau tracer, and the above image characteristics should be considered in the design of longitudinal preclinical tau image studies.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

et al. 2020

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“…Speculatively, this could indicate different predictive capability of TSPO µPET depending on whether tau or amyloid-β accumulation is the primary driver of microgliosis. Regarding tau mouse models, our observation of higher tau accumulation in mice with early microglial activation is in line with findings of associated tau and neuroinflammation in the forebrain of rTg4510 tau mice [32]. Our data also fit with the observations of attenuated NFT accumulation, reduced neuronal degeneration, and averted cognitive deterioration after pharmacological ablation of senescent microglial and astroglial cells in PS19 mice [33], as well as fitting with the increased tau pathology occurring along with NLRP3 inflammasome activation [7].…”

Section: Discussionsupporting

confidence: 89%

Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

Eckenweber

Luque

Blume

et al. 2020

Preprint

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Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in 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 18kDa 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 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 6.7/6.3 months. Conclusions: Monitoring of microglial activation in P301S tau transgenic mice by TSPO 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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“…P301S and P301L lines (transgenic for a human 4 repeat tau isoform) [6,[52][53][54], which have become important tools to study the mechanisms of abnormal tau aggregation and deposition in FTD (4 repeat tau) [61] and AD (3 and 4 repeat tau) [25, 33,41]. In the P301L 4 (Thy 1.2, pR5 line) [11,18], P301L (CaMKIIa) [23,43,62] and P301L (tetO) [14] mouse models, tau deposits begin forming before 3 months-of-age in neurons in the entorhinal cortex, hippocampus and later in the cortex, and amygdala; with neuroinflammation and impaired memory functions in hippocampus-and amygdala-dependent tasks manifesting at a later stage [49,50,67]. Brain atrophy and white matter changes indicating neurodegeneration were reported in P301L (CaMKIIa) mouse line around 9 months-of-age [16,23,43,62], which was driven by factors additional to human tau overexpression.…”

Section: Introductionmentioning

confidence: 99%

“…In the P301L 4 (Thy 1.2, pR5 line) [11,18], P301L (CaMKIIa) [23,43,62] and P301L (tetO) [14] mouse models, tau deposits begin forming before 3 months-of-age in neurons in the entorhinal cortex, hippocampus and later in the cortex, and amygdala; with neuroinflammation and impaired memory functions in hippocampus-and amygdala-dependent tasks manifesting at a later stage [49,50,67]. Brain atrophy and white matter changes indicating neurodegeneration were reported in P301L (CaMKIIa) mouse line around 9 months-of-age [16,23,43,62], which was driven by factors additional to human tau overexpression. However, unlike in human patients with tauopathies, brain calcifications have not been reported in transgenic mouse models of human disease.…”

Section: Introductionmentioning

confidence: 99%

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

Zarb

Kuhn

et al. 2019

Preprint

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Brain calcification is associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of intracranial calcification in transgenic P301L mice overexpressing 4 repeat tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates were assessed using in vivo/ex vivo magnetic resonance imaging (MRI) with a gradient recalled echo sequence and micro computed tomography (μCT). Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions.Occurrence of diamagnetic susceptibility lesions in the hippocampus, increased with age.Immunochemical staining of brain sections revealed bone protein-positive deposits. Furthermore, intra-neuronal and vessel-associated protein-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus. Protein-containing nodules were detected also in the thalamus in the absence of phosphorylated-tau deposition. In contrast, osteocalcin-containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated-tau. In summary, MRI and µCT demonstrated imaging pattern of intracranial calcification, concomitant with immunohistochemical evidence of formation of protein deposits containing bone proteins along with phosphorylated-tau in the P301L mouse model of human tauopathy. The P301L mouse model may thus serve as a future model to study the pathogenesis of brain calcifications in tauopathies.3

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In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510

Cited by 64 publications

References 55 publications

Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

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