Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

Shi, Yang; Murzin, Alexey G.; Falcon, Benjamin; Epstein, A.; Machin, Jonathan; Tempest, Paul; Newell, Kathy L.; Vidal, Rubén; Garringer, Holly J.; Sahara, Naruhiko; Higuchi, Makoto; Ghetti, Bernardino; Jang, Ming‐Kuei; Scheres, S.H.W.; Goedert, Michel

doi:10.1007/s00401-021-02294-3

Cited by 116 publications

(138 citation statements)

References 51 publications

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“…In vitro binding data for CBD2115, PM-PBB3, PI2640, and MK6240 in postmortem cortical brain tissue from AD, PSP, or CBD subjects indicate differences in binding properties between the different tau tracers. 17 , 34 , 39 , 40 [ 3 H-]MK6240 has shown a 100 times higher affinity in AD brain tissue compared to both PSP and CBD brain tissue. 33 10 and 2 times lower K d binding values in PSP and CBD tissues have been reported for [ 3 H-]CBD2115 compared to [ 3 H-]MK6240.…”

Section: Discussionmentioning

confidence: 99%

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils

Zhou

Nordberg

et al. 2021

ACS Chem. Neurosci.

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Alzheimer’s disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer’s disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.

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Section: Discussionmentioning

confidence: 99%

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils

Zhou

Nordberg

et al. 2021

ACS Chem. Neurosci.

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“…Using cryo-electron microscopy (cryo-EM), it has been recently determined that the fold of the core of Tau filaments in sporadic and familial AD differs from those in PiD and CBD [ 3 , 10 – 12 , 16 , 64 ]. Furthermore, although neurofibrillary tangles (NFTs) in AD, CTE, and primary age-related tauopathy (PART) [ 6 , 8 , 43 ] incorporate all six Tau isoforms, the fold of the core of Tau filaments is identical in AD and PART and different from that in CTE [ 12 , 16 , 55 ]. Thus, the Alzheimer Tau fold may be found in the presence (AD) or in the absence (PART) of amyloid β (Aβ); however, the specific role of Aβ in the pathogenesis of Tau aggregation in AD remains undetermined.…”

Section: Introductionmentioning

confidence: 99%

Structure of Tau filaments in Prion protein amyloidoses

et al. 2021

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In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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“…PET assisted with the tau tracer [ 18 F]PM-PBB has been shown to detect different patterns in patients with PSP and CBD compared to AD, indicating a role in differential diagnosis 9 . Recent cryo-EM has shown that PM-PBB3 binds to tau fibrils in AD brain 80 . An In silico study reported THK5351 probes, T807 binding to different sites on tau fibrils 4,81 as well as off-target binding sites 79 .…”

Section: Discussionmentioning

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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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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Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

Cited by 116 publications

References 51 publications

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils

Structure of Tau filaments in Prion protein amyloidoses

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

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