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

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 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.

Язык: Английский

Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240 DOI Creative Commons
Peter Kunach, Jaime Vaquer‐Alicea, Matthew S. Smith

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

17
Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold DOI Creative Commons
Ujjayini Ghosh, Eric Tse, Hyunjun Yang

и другие.

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Июнь 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.

Язык: Английский

Процитировано

8
A Cooperative Model for Symmetric Ligand Binding to Protein Fibrils DOI Creative Commons

Matthew S. Smith,

William F. DeGrado, Michael Grabe

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

A hallmark of neurodegenerative diseases like Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE) is the presence toxic protein aggregates in neurons. In AD CTE specifically, tau forms insoluble fibrils that are hundreds nanometers length. Intriguingly, recent experimental structures suggest ligands disaggregator EGCG positron emission tomography (PET) tracers GTP-1 MK-6240 bind to long stacks reflecting symmetry across many binding sites. these stacks, each ligand makes more contact with its mates than it does protein. To interpret molecules new ligands, we must understand effects cooperativity between sites entropy coming from number Here, investigate a nearest-neighbors model use statistical mechanics derive isotherms for saturation competition experiments. This allows us relate measured EC 50 so IC values intrinsic affinity single site ways resembling Cheng-Prusoff Equation. Depending on degree molecular species, this permits solutions lack steep curves expected cooperative systems even 2-site systems. We finally consider conditions fibril's detection PET scan practical matters fitting model's parameters data.

Язык: Английский

Процитировано

0
Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies DOI Creative Commons
Nicolò Bisi, Luca Pinzi, Giulio Rastelli

и другие.

Drug Discovery Today, Год журнала: 2025, Номер unknown, С. 104352 - 104352

Опубликована: Апрель 1, 2025

Tauopathies, including Alzheimer's disease (AD), Pick's (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are characterized by the misfolding pathological aggregation of tau protein, leading to neurodegeneration. Although pathogenesis these diseases is still a matter for debate, formation amyloid inclusions represents only histopathological hallmark available. Tau not same in terms structure morphology, different tauopathies polymorphs. Remarkably, selective detection polymorphs crucial differential diagnosis, monitoring evaluation potential harmfulness polymorphs, with significant impact on drug discovery. This review discusses recent advances development imaging probes designed forms associated specific tauopathies. We explore application compounds that can target characteristic AD, PiD, PSP CBD. In particular, we focus discussing probes' selectivity sensitivity distinguishing between tauopathy-associated preclinical settings. The progress weaknesses this field discussed, guide researchers identifying accurate potent diagnosis neurodegenerative diseases.

Язык: Английский

Процитировано

0
Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer’s Disease Fold DOI Creative Commons
Ujjayini Ghosh, Eric Tse, Hyunjun Yang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 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.

Язык: Английский

Процитировано

0