High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies

Tagai, Kenji; Ono, Masahiro; Kubota, Manabu; Kitamura, Soichiro; Takahata, Keisuke; Seki, Chie; Takado, Yuhei; Shinotoh, Hitoshi; Sano, Yasunori; Yamamoto, Yasuharu; Matsuoka, Kiwamu; Takuwa, Hiroyuki; Shimojo, Masafumi; Takahashi, Manami; Kawamura, Kazunori; Kikuchi, Tatsuya; Okada, Maki; Akiyama, Haruhiko; Suzuki, Hisaomi; Onaya, Mitsumoto; Takeda, Takahiro; Arai, Kimihito; Arai, Nobutaka; Araki, Nobuyuki; Saito, Yuko; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Mishra, Sushil Kumar; Yamaguchi, Yoshiki; Kimura, Yasuyuki; Ichise, Masanori; Tsutsumi, Yutaka; Zhang, Ming‐Rong; Suhara, Tetsuya; Shigeta, Masahiro; Sahara, Naruhiko; Higuchi, Makoto; Shimada, Hitoshi

doi:10.1016/j.neuron.2020.09.042

Cited by 192 publications

(238 citation statements)

References 95 publications

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“…Absolute MM/GBSA energies of PM-PBB3 are similar for both Tau AD and Tau PiD (−34.2 kcal·mol −1 for Tau AD and −34.3 kcal·mol −1 for Tau PiD ) ( Figure 5 A,B), confirming that PM-PBB3 binds to both kinds of tau filaments. This is in the agreement with recent experimental study that indicates binding of PM-PBB3 to Tau PiD and Tau AD is nearly similar [ 16 ]. On the other hand, the relative binding order of PM-PBB3 illustrates unique features of the Tau PiD protofibril when compared to that of Tau AD .…”

Section: Resultssupporting

confidence: 93%

“…In addition, this approach can be applied to the interaction of PET tracers with non-tauopathy off-targets, such as MAO-A/-B and other dementia/neurodegenerative proteins (amyloid-β or α-synuclein). Since previous studies confirmed relatively low affinities of tau tracers, [ 11 C]PBB3 and [ 18 F]PM-PBB3, for MAO-A/B and α-synuclein by in vitro radioligand binding assay [ 16 , 35 , 36 ], it will be interesting to perform side-by-side validation with both an in vitro assay and an MM/GBSA approach.…”

Section: Resultsmentioning

confidence: 99%

“…Current tau PET tracers such as [ 18 F]AV-1451 ([ 18 F]flortaucipir), [ 18 F]THK5351, [ 11 C]PBB3, [ 18 F]PM-PBB3 and [ 18 F]MK-6240 ( Figure 1 A) have been successful in the in vivo evaluation of tau pathology of AD brains [ 9 , 11 , 16 , 27 , 28 ]. [ 18 F]PM-PBB3 PET imaging also was demonstrated to be useful for the differential diagnosis of non-AD dementia patients (e.g., PSP, CBD, and Pick disease) [ 16 ]. However, binding of other tracers to tau filaments derived from non-AD brains is still under investigation.…”

Section: Resultsmentioning

confidence: 99%

“…Most recent findings with both clinical and pre-clinical studies of [ 18 F]PM-PBB3 imaging revealed the feasibility of using PM-PBB3 to recognize tau pathologies in both AD and non-AD brains including Pick’s disease [ 16 ]. To confirm PM-PBB3 binding to Tau AD and Tau PiD and to determine preference through binding affinity, we calculated binding affinities of PM-PBB3 for both Tau AD and Tau PiD by docking and MM/GBSA calculations.…”

Section: Resultsmentioning

confidence: 99%

“…Tau tracers are mostly designed according to β-sheet binding properties and theoretically label all filamentous tau aggregates (e.g., neurofibrillary tangles (NFTs), neuropil threads, tufted astrocytes, astrocytic plaques, and coiled bodies). Several PET tracers for detecting filamentous tau inclusions, such as [ 11 C]PBB3, [ 18 F]PM-PBB3, [ 18 F]AV1451, [ 18 F]THK5351, [ 18 F]MK-6240, [ 18 F]R06958948, [ 18 F]GTP-1, and [ 18 F]PI-2620, were developed and have been applied to human subjects [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. The distribution of the bound tracers recapitulated Braak NFT staging [ 17 ] in AD brains, suggesting in vivo imaging-based staging of tau pathologies.…”

Section: Introductionmentioning

confidence: 99%

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Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

Mishra

Yamaguchi

Higuchi

et al. 2020

IJMS

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In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

Mishra

Yamaguchi

Higuchi

et al. 2020

IJMS

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Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers

et al. 2023

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The deposition of highly phosphorylated and aggregated tau is a characteristic of tauopathies, including Alzheimer's disease. It has long been known that different isoforms of tau are aggregated in different cell types and brain regions in each tauopathy. Recent advances in analytical techniques revealed the details of the biochemical and structural biological differences of tau specific to each tauopathy. In this review, we explain recent advances in the analysis of post‐translational modifications of tau, particularly phosphorylation, brought about by the development of mass‐spectrometry and Phos‐tag technology. We then discuss the structure of tau filaments in each tauopathy revealed by the advent of cryo‐EM. Finally, we describe the progress in biofluid and imaging biomarkers for tauopathy. This review summarizes current efforts to elucidate the characteristics of pathological tau and the landscape of the use of tau as a biomarker to diagnose and determine the pathological stage of tauopathy.

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Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders

Sahara,

Higuchi

2023

FEBS Open Bio

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Tauopathies, characterized by fibrillar tau accumulation in neurons and glial cells, constitute a major neuropathological category of neurodegenerative diseases. Neurofibrillary tau lesions are strongly associated with cognitive deficits in these diseases, but the causal mechanisms underlying tau‐induced neuronal dysfunction remain unresolved. Recent advances in cryo‐EM examination have revealed various core structures of tau filaments from different tauopathy patients, which can be used to classify tauopathies. In vivo visualization of tau pathology is now available using several tau PET tracers. Among these radioprobes, PM‐PBB3 allows high‐contrast imaging of tau deposits in the brains of patients with diverse disorders and tauopathy mouse models. Selective degradation of pathological tau species by the ubiquitin‐proteasome system or autophagy machinery is a potential therapeutic strategy. Alternatively, the non‐cell‐autonomous clearance of pathological tau species through neuron‐glia networks could be reinforced as a disease‐modifying treatment. In addition, the development of neuroinflammatory biomarkers is required for understanding the contribution of immunocompetent cells in the brain to preventing neurodegeneration. This review provides an overview of the current research and development of diagnostic and therapeutic agents targeting divergent tau pathologies.

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High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies

Abstract: All rights reserved. No reuse allowed without permission.

Cited by 192 publications

References 95 publications

Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers

Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders

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