Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer’s Disease Fold DOI Creative Commons
Ujjayini Ghosh, Eric Tse, Hyunjun Yang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 3, 2024

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among the complex clinical features including musculoskeletal, neurological and cardiovascular disabilities, individuals with DS have an increased risk developing progressive dementia early onset Alzheimer's Disease (AD). This attributed to gene dosage amyloid-β (Aβ) precursor protein gene, formation self-propagating Aβ tau prion conformers, deposition neurotoxic plaques neurofibrillary tangles. Tau amyloid fibrils previously been established adopt many distinct conformations across different neurodegenerative conditions. Here we report characterization brain samples from four cases spanning 36 63 years age spectral confocal imaging conformation-specific dyes cryo-electron microscopy (cryo-EM) determine structures isolated fibrils. High-resolution reveal paired helical filament (PHF) straight (SF) that are identical those determined AD. The PHFs SFs made two C-shaped protofilaments cross-β/β-helix motif. Similar filaments AD cases, most adopted PHF form, while minority (~20%) formed SFs. Samples youngest individual no documented had sparse deposits. To isolate for cryo-EM this challenging sample used novel affinity-grid method involving graphene-oxide surface derivatized anti-tau antibodies. improved isolation revealed primarily minor population chronic traumatic encephalopathy type II-like were present in case. These findings expand similarities between molecular level, providing insight into their related pathologies potential targeting folds small-molecule therapeutics diagnostics.

Language: Английский

Local structural preferences in shaping tau amyloid polymorphism DOI Creative Commons
Nikolaos Louros, Martin Wilkinson,

Grigoria Tsaka

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 3, 2024

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, extent to which intrinsic structural tendencies cores contribute remains uncertain. Using combination experimental approaches, we here identify new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif Repeat 4), as significant contributor polymorphism. Calculation per-residue contributions stability different pathologic structures plays central role in preserving integrity polymorphs. Consistent with this, cryo-EM analysis fibrils formed from synthetic peptide shows sequence adopts alternative closely correspond disease-associated strains. Furthermore, in-cell experiments revealed deletion hampers cellular seeding efficiency aggregates extracted Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal these tauopathies. Together, our results highlight importance propensity core segments determine structure cells, propagating

Language: Английский

Citations

10
Inducers and modulators of protein aggregation in Alzheimer's disease - Critical tools for understanding the foundations of aggregate structures DOI Creative Commons
Kerry Sun, Sue‐Ann Mok

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00512 - e00512

Published: Jan. 1, 2025

Language: Английский

Citations

1
Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold DOI Creative Commons
Ujjayini Ghosh, Eric Tse, Hyunjun Yang

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: June 12, 2024

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk developing progressive dementia early-onset Alzheimer's disease (AD). This attributed to the gene dosage amyloid-β (Aβ) precursor protein gene, formation self-propagating Aβ tau prion conformers, deposition neurotoxic plaques neurofibrillary tangles. Tau amyloid fibrils previously been established adopt many distinct conformations across different neurodegenerative conditions. Here, we report characterization brain samples from four cases spanning 36-63 years age spectral confocal imaging conformation-specific dyes cryo-electron microscopy (cryo-EM) determine structures isolated fibrils. High-resolution revealed paired helical filament (PHF) straight (SF) that were identical those determined AD cases. The PHFs SFs are made two C-shaped protofilaments, each containing cross-β/β-helix motif. Similar filaments cases, most adopted PHF form, while minority (approximately 20%) formed SFs. Samples youngest individual no documented had sparse deposits. To isolate for cryo-EM this challenging sample used novel affinity-grid method involving graphene oxide surface derivatized anti-tau antibodies. improved isolation primarily minor population chronic traumatic encephalopathy type II-like present in case. These findings expand similarities between molecular level, providing insight into related pathologies potential targeting folds small-molecule therapeutics diagnostics.

Language: Английский

Citations

7
Docking for Molecules That Bind in a Symmetric Stack with SymDOCK DOI Creative Commons

Matthew S. Smith,

Ian Knight,

Rian Kormos

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(2), P. 425 - 434

Published: Jan. 8, 2024

Discovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of great current interest. In recent structures, bind in stacks fibrils to reflect rotational and translational symmetry fibril itself; these make few interactions with protein but interact extensively each other. To exploit this stacking, we developed SymDOCK, a method dock molecules that follow protein's symmetry. For prospective ligand pose, apply operation generate self-interacting fibril-interacting stack, checking doing so will not cause clash between original molecule its image. Absent clash, retain pose add ligand-ligand van der Waals energy ligand's docking score (here using DOCK3.8). We can check geometries energies implementation ANI, neural-network-based quantum-mechanical evaluation stacking energies. retrospective calculations, reproduce poses three PET tracers whose structures have been determined. More convincingly,

Language: Английский

Citations

5
Comparison Between Brain and Cerebellar Autoradiography Using [18F]Flortaucipir, [18F]MK6240, and [18F]PI2620 in Postmortem Human Brain Tissue DOI
Antonio Aliaga, Joseph Therriault, Kely Quispialaya

et al.

Journal of Nuclear Medicine, Journal Year: 2024, Volume and Issue: unknown, P. jnumed.124.267539 - jnumed.124.267539

Published: Oct. 30, 2024

Our objective was to evaluate the in vitro binding properties of [

Language: Английский

Citations

4
Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer’s disease and primary age-related tauopathy DOI Creative Commons
Nil Saez-Calveras, Jaime Vaquer-Alicea, Charles L. White

et al.

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 8, 2025

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, associated cognitive impairment and accumulation. In this study, we explored assembly conformation ET patients pathology using cytometry-based biosensor assays. These assays quantify seeding activity present brain homogenates detecting conversion intracellular tau-fluorescent protein fusions from soluble to an aggregated state. Pathogenic assemblies exhibit barriers, where specific structure cannot serve as template for native monomer if amino acid sequences incompatible. We recently leveraged species barrier define systematically substituting alanine (Ala) into measuring its incorporation seeded aggregates within cells. This Ala scan precisely classified seeds various tauopathies. analyzed 18 patient brains pathology, robust 9 (50%) predominantly localized temporal pole cortex. further examined 8 these cases found that requirements were identical those Alzheimer's disease (AD) primary age-related tauopathy (PART), other tauopathies, such corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), supranuclear palsy (PSP). findings indicate pathologically confined subset significant cores seen AD PART. could facilitate more precise diagnosis targeted therapies presenting impairment.

Language: Английский

Citations

0
Tau PET Imaging With [18F]MK‐6240: Limited Affinity for Primary Tauopathies and High Specificity for Alzheimer's Disease DOI Creative Commons
Thomas Gérard, Lise Colmant, Vincent Malotaux

et al.

European Journal of Neurology, Journal Year: 2025, Volume and Issue: 32(2)

Published: Feb. 1, 2025

ABSTRACT Introduction Second‐generation tau‐PET tracers like [ 18 F]MK‐6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while has demonstrated excellent sensitivity AD tauopathy, data assessing its specificity binding in non‐AD tauopathies still scarce. Methods Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) cognitive status. We quantified mesiotemporal (MTL) neocortical signal 28 Aβ− cognitively impaired (CI) patients presenting various neurodegenerative disorders. Tau‐PET quantifications compared with unimpaired (CU) subjects ( n = 51) Aβ+ CI 77). Results Among the subjects, only five presented significant isolated signal, most of them being suspected primary age‐related tauopathy (PART). Only two (7%) positive diagnosed fronto‐temporal degeneration (FTD). The results all remaining comparable CU population, including eight other FTD patients. Importantly, 4R‐only (CBD PSP) sv‐PPA negative. Conclusion a special affinity involving 3R/4R paired helical filaments: AD, PART (Aβ− MTL‐restricted signal) some forms do not exhibit cortical signal. Positive scans therefore highly specific Based those previous results, we propose diagnostic flowchart MCI or another which may significantly reduce need PET CSF measurement.

Language: Английский

Citations

0
Investigating the neural network correlates of apathy, disinhibition, and executive dysfunction in active-duty United States Special Operations Forces DOI
Natalie Gilmore, Isabella R. McKinney, Chieh-En Jane Tseng

et al.

Brain Imaging and Behavior, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Language: Английский

Citations

0
Advanced Tau Imaging in Alzheimer’s Disease and Other Types of Dementia DOI
Kenji Tagai, Makoto Higuchi

Neuromethods, Journal Year: 2025, Volume and Issue: unknown, P. 33 - 43

Published: Jan. 1, 2025

Language: Английский

Citations

0
Cryo-EM structures of pathogenic fibrils and their impact on neurodegenerative disease research DOI
Tiffany W. Todd,

Naeyma N. Islam,

Casey Cook

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(14), P. 2269 - 2288

Published: June 3, 2024

Language: Английский

Citations

3