Tauopathies: new perspectives and challenges

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: April 7, 2022

Abstract Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with range phenotypes that include cognitive/behavioral-disorders, movement disorders, language and non-specific amnestic symptoms in advanced age. Pathologically, be classified based on the predominant tau isoforms inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) blood-based biomarkers have potential to used as routine diagnostic strategy evaluation patients tauopathies. As strongly linked neuropathologically genetically protein abnormalities, there is growing interest pursuing tau-directed therapeutics for disorders. Here we synthesize emerging lessons from clinical, pathological, genetic, experimental studies toward unified concept these may accelerate therapeutics. Conclusions Since still untreatable diseases, efforts been made depict clinical pathological characteristics, identify biomarkers, elucidate underlying pathogenesis achieve early diagnosis develop disease-modifying therapies.

Language: Английский

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

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 697 - 708

Published: March 16, 2021

Abstract Tau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). comprise paired helical straight filaments (PHFs SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD other tau proteinopathies. Since it not known where the folds ligands bind, we used electron cryo-microscopy (cryo-EM) to determine binding sites Alzheimer fold. We identified two major β-helix PHFs SFs third site C-shaped cavity SFs. In addition, report that from posterior cortical atrophy (PCA) primary age-related tauopathy (PART) are identical those AD. support, fluorescence labelling showed intraneuronal inclusions AD, PART PCA. Knowledge modes may lead development new with increased specificity activity. show cryo-EM identify small molecules amyloid filaments.

Language: Английский

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Interpretable learning based Dynamic Graph Convolutional Networks for Alzheimer’s Disease analysis

Information Fusion, Journal Year: 2021, Volume and Issue: 77, P. 53 - 61

Published: July 31, 2021

Language: Английский

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PET Imaging of Neuroinflammation in Alzheimer’s Disease

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 16, 2021

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with central pathologies patients animal models. Recent single-cell sequencing transcriptomics indicate dynamic disease-associated microglia astrocyte profiles disease. Mitochondrial 18-kDa translocator protein is most widely investigated target for imaging. New generation tracers improved performance been developed evaluated along tau amyloid assessing progression continuum. Given that not exclusively expressed glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 purinergic P2X7 P2Y12 fractalkine triggering receptor on myeloid cells 2, advanced glycation end products. Promising should demonstrate a higher specificity cellular locations exclusive expression or activation status (pro- anti-inflammatory) highly specific ligand to enable vivo brain In this review, we summarised recent advances development outlook promising future.

Language: Английский

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Tau deposition patterns are associated with functional connectivity in primary tauopathies

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 15, 2022

Abstract Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. assumed to spread prion-like across connected neurons, but mechanisms tau propagation are largely elusive characterized not only by also astroglial oligodendroglial accumulation. Here, we assess whether connectivity associated with 4R-tau deposition patterns combining resting-state fMRI connectomics both 2 nd generation 18 F-PI-2620 tau-PET 46 patients clinically diagnosed tauopathies post-mortem cell-type-specific regional assessments from two independent palsy patient samples ( n = 97 96). We find that inter-regional higher correlation levels tauopathies. In cell-type specific assessments, this association stronger for than or tau, suggesting primarily Using further patient-level subcortical epicenters. Together, current study provides combined vivo histopathological evidence brain

Language: Английский

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Near-infrared fluorescence lifetime imaging of amyloid-β aggregates and tau fibrils through the intact skull of mice

Nature Biomedical Engineering, Journal Year: 2023, Volume and Issue: 7(3), P. 270 - 280

Published: Feb. 6, 2023

Language: Английский

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Imaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2540 - 2557.e8

Published: June 5, 2024

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while vivo detection pathologies these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing deposits the brains living subjects. In optical positron emission tomography (PET) imaging mouse marmoset models demonstrated that C05-05 captured dynamic propagation fibrillogenesis along neural pathways, followed by disruptions structures. High-affinity binding 18F-C05-05 to aggregates human brain tissues was also proven vitro assays. Notably, PET-detectable signals were intensified midbrains PD DLB patients as compared healthy controls, providing first demonstration illnesses. Collectively, propose new technology offering neuropathology-based translational assessments allied disorders toward diagnostic therapeutic research development.

Language: Английский

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Current Progress and Future Directions in Non-Alzheimer’s Disease Tau PET Tracers

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 111 - 127

Published: Jan. 6, 2025

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [18F]FDDNP, [11C]PBB3, [18F]flortaucipir, [18F]THK series, for vivo detection has marked a significant breakthrough fields neuroscience radiopharmaceuticals, creating robust new category labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other PET tracers with improved binding properties have been developed using various chemical scaffolds to target three-repeat/four-repeat (3R/4R) folds AD. In 2020, [18F]flortaucipir was approved U.S. Food Drug Administration imaging pathology adult patients cognitive deficits undergoing evaluation Despite remarkable progress development AD tracers, agents rare (4R [predominantly expressing 4R isoform], involved progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, 3R such as Pick's disease) remain substantially underdeveloped. this review, we discuss recent tracer development, particular emphasis on clinically validated their potential use tauopathies. Additionally, highlight critical need further specifically designed tauopathies, an area that remains significantly underexplored despite its importance advancing understanding diagnosis these disorders.

Language: Английский

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Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(10), P. 601 - 620

Published: Aug. 23, 2021

Language: Английский

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An App knock-in rat model for Alzheimer’s disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments

Cell Research, Journal Year: 2021, Volume and Issue: 32(2), P. 157 - 175

Published: Nov. 17, 2021

Abstract A major obstacle in Alzheimer’s disease (AD) research is the lack of predictive and translatable animal models that reflect progression drug efficacy. Transgenic mice overexpressing amyloid precursor protein ( App ) gene manifest non-physiological ectopic expression APP its fragments brain, which not observed AD patients. The knock-in circumvented some these problems, but they do exhibit tau pathology neuronal death. We have generated a rat model, with three familiar mutations humanized Aβ sequence knocked into gene. Without altering levels full-length other fragments, this model exhibits pathologies resembling those human patients: deposit plaques relevant brain regions, microglia activation gliosis, progressive synaptic degeneration AD-relevant cognitive deficits. Interestingly, we pathology, apoptosis necroptosis atrophy, phenotypes rarely seen models. This may serve as useful tool for research, identifying new targets biomarkers, testing therapeutics.

Language: Английский

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