SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy

Ni, Ruiqing; Zarb, Yvette; Kuhn, Gisela; Müller, Ralph; Yundung, Yankey; Nitsch, Roger M.; Kulic, Luka; Keller, Annika; Klohs, Jan

doi:10.1007/s10334-020-00855-3

Cited by 20 publications

(31 citation statements)

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“…In P301L as well as in other tauopathy mouse models, the neurofibrillary tangle is rear and less fibrillar structure is present in the mouse brain 26,34,84 . The cortical and hippocampal signals detected by vMSOT in vivo and ex vivo using PBB5 are in accordance with immunofluorescence staining results, and with the known tau distribution in the P301L mouse brain 84,86 . NIRF imaging using PBB5 and PET using [ 11 C]mPBB5, respectively, have been previously reported for mapping tau deposition in the brain stem and spinal cord of P301S mice 33 .…”

Section: Discussionsupporting

confidence: 85%

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Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

Vagenknecht

Ono

Luzgin

et al. 2021

Preprint

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AimAbnormal tau accumulation plays an important role in tauopathy diseases such as Alzheimer’s disease and Frontotemporal dementia. There is a need for high-resolution imaging of tau deposits at the whole brain scale in animal models. Here, we demonstrate non-invasive whole brain imaging of tau-targeted PBB5 probe in P301L model of 4-repeat tau at 130 μm resolution using volumetric multi-spectral optoacoustic tomography (vMSOT).MethodsThe binding properties of PBB5 to 4-repeat K18 tau and Aβ42 fibrils were assessed by using Thioflavin T assay and surface plasmon resonance assay. We identified the probe PBB5 suitable for vMSOT tau imaging. The imaging performance was first evaluated using postmortem human brain tissues from patients with Alzheimer’s disease, corticobasal degeneration and progressive supranuclear palsy. Concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice. Ex vivo measurements on excised brains along with multiphoton microscopy and immunofluorescence staining of tissue sections were performed for validation. The spectrally-unmixed vMSOT data was registered with MRI atlas for volume-of-interest analysis.ResultsPBB5 showed specific binding to recombinant K18 tau fibrils, Alzheimer’s disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brain. i.v. administration of PBB5 in P301L mice led to retention of the probe in tau-laden cortex and hippocampus in contrast to wild-type animals, as also confirmed by ex vivo vMSOT, epi-fluorescence and multiphoton microscopy results.ConclusionvMSOT with PBB5 facilitates novel 3D whole brain imaging of tau in P301L animal model with high-resolution for future mechanistic studies and monitoring of putative treatments targeting tau.

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Section: Discussionsupporting

confidence: 85%

“…Table 1). Sections were counterstained using DAPI 86 . The brain sections were imaged at × 20 magnification using Axio Oberver Z1 and at × 63 magnification using a Leica SP8 confocal microscope (Leica, Germany) for colocalization of PBB5 with AT-8.…”

Section: Ex Vivo Immunofluorescence and Confocal Imagingmentioning

confidence: 99%

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

Vagenknecht

Ono

Luzgin

et al. 2021

Preprint

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“…Increased MD most likely results from loss of neurons and dendrites, which result in an increase in extracellular space and elevated water diffusivity within these regions [24]. Neuronal loss and gliosis have been both described to occur in some grey matter regions of P301L mice [29, 38]. Pronounced changes in DTI metrics have been observed in regions of strong tau expression such as the hippocampus and cortex [29, 38, 57].…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Neuronal loss and gliosis have been both described to occur in some grey matter regions of P301L mice [29, 38]. Pronounced changes in DTI metrics have been observed in regions of strong tau expression such as the hippocampus and cortex [29, 38, 57]. However, in previous studies a correlation between DTI and tau burden in rTg4510 mice was not established [34, 36].…”

Section: Discussion/conclusionmentioning

confidence: 99%

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DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy

Massalimova

Nitsch³

et al. 2020

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Introduction: Increased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months-of-age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data. Methods: Hemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) maps. VBA on the entire brain were performed using SPM8 and SPM Mouse toolbox. Initially, all DTI maps were co-registered with Allen mouse brain atlas to bring them to one common coordinate space. In VBA, co-registered DTI maps were normalized and smoothed in order to perform two-sample t-tests to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions-of-interests were computed with co-registered DTI maps and labels in Allen mouse brain atlas. After, the same two-sample t-tests were executed on the estimated average values. Results: We made reconstructed DTI data and VBA and ABA pipeline publicly available. With VBA, we found microstructural changes in the white matter in hemizygous P301L mice compared to non-transgenic littermates. In contrast, more pronounced and brain-wide spread changes were observed in VBA when comparing homozygous P301L mice with non-transgenic littermates. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD and AD were increased compared to hemizygotes and non-transgenic littermates. Discussion/Conclusion: High resolution ex vivo DTI demonstrated brain-wide microstructural changes in the P301L mouse model of human tauopathy. The comparison between hemizygous and homozygous P301L mice revealed a gene-dose dependent effect on DTI metrics. The publicly available computational data analysis pipeline can provide a platform for future mechanistic and longitudinal studies.

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Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

Vagenknecht

Luzgin

Ono

et al. 2022

Eur J Nucl Med Mol Imaging

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Purpose Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer’s disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired. Methods We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 μm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). In vitro probe characterization, concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice, followed by ex vivo validation using AT-8 antibody for phosphorylated tau. Results PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer’s disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Dose-dependent optoacoustic and fluorescence signal intensities were observed in the mouse brains following i.v. administration of different concentrations of PBB5. In vivo vMSOT brain imaging of P301L mice showed higher retention of PBB5 in the tau-laden cortex and hippocampus compared to wild-type mice, as confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, and immunofluorescence staining. Conclusions We demonstrated non-invasive whole-brain imaging of tau in P301L mice with vMSOT system using PBB5 at a previously unachieved ~ 115 μm spatial resolution. This platform provides a new tool to study tau spreading and clearance in a tauopathy mouse model, foreseeable in monitoring tau targeting putative therapeutics.

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SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy

Cited by 20 publications

References 42 publications

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

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