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

Abstract

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.

Recent Developments in Positron Emission Tomography Tracers for Proteinopathies Imaging in Dementia

“…Animal models, such as P301L and P301S, that recapitulate pathological features of 4R tauopathy have been developed with mutations in the MAPT gene, ( Lewis et al, 2000 ; Gotz et al, 2001 ; SantaCruz et al, 2005 ; Spires et al, 2006 ), as well as hTau and knock in animal models ( Saito et al, 2019 ; Hosokawa et al, 2021 ). The in vivo imaging of tau has been demonstrated in animal models using [ 18 F]APN-1607, [ 11 C]PBB3, [ 11 C]mPBB5, [ 18 F]THK5117, and [ 18 F]JNJ64349311 ( Maruyama et al, 2013 ; Brendel et al, 2016 , 2018 ; Declercq et al, 2017 ; Ishikawa et al, 2018 ; Ni et al, 2018 ; Tagai et al, 2020 ; Vagenknecht et al, 2021 ), as well as SPECT using [ 123 I]PIP-NHMe ( Watanabe et al, 2021 ). It is noted that [ 18 F]flortaucipir did not detect tau in the rTg4510 (P301L) 4R-tau mouse model ( Marquié et al, 2015 ; Ni et al, 2018 ).…”

Magnetic Resonance Imaging in Tauopathy Animal Models

“…Positron emission tomography (PET) imaging of tau in tauopathy mouse models using various tau-targeted radioligands has been established ( Maruyama et al, 2013 ; Brendel et al, 2016 ; Ono et al, 2017 ; Ishikawa et al, 2018 ; Ni et al, 2018 ; Tagai et al, 2020 ; Chaney et al, 2021 ; Cao et al, 2022 ). In addition, fluorescence imaging, two-photon microscopy, and photoacoustic imaging methods have been developed for in vivo mapping of tau accumulation in animal models ( Wu et al, 2018 ; Calvo-Rodriguez et al, 2019 ; Ni et al, 2020a ; Vagenknecht et al, 2021 ). To date, a few MRI tau imaging studies have been reported assisted with contrast agents ( Table 1 ).…”

Multimodal Contrast Agents for Optoacoustic Brain Imaging in Small Animals

“…OA microscopy with Congo red has been used for the detection of amyloid-β plaques and cerebral amyloid angiopathy in the APP/PS1 mouse model (Hu et al, 2009;Zhou et al, 2021). OA tomography with chemical dye PBB5 (PBB3 derivative) for detection of β-sheet-containing tau deposits in the P301L 4-repeat tau mouse model has been reported (Ono et al, 2017;Vagenknecht et al, 2021). It is foreseeable that OA tomography pipeline with the deep brain region detection capability will be applied together with OA/fluorescence β-sheet-binding dyes to image other proteiopathy disease models, such as Parkinson's disease mouse model with α-synuclein accumulation and the amyotrophic lateral sclerosis animal model with TAR DNA-binding protein 43 deposits.…”