Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer’s disease and primary age-related tauopathy

Acta Neuropathologica, Год журнала: 2025, Номер 149(1)

Опубликована: Янв. 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.

Язык: Английский

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Current Advancements in Digital Neuropathology and Machine Learning for the Study of Neurodegenerative Diseases

American Journal Of Pathology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Therapy of swallowing and speech problem in patients with progressive supranuclear palsy

Srpski arhiv za celokupno lekarstvo, Год журнала: 2025, Номер 153(1-2), С. 78 - 82

Опубликована: Янв. 1, 2025

Introduction. Progressive supranuclear palsy (PSP) is a rare form of neurodegenerative extrapyramidal disease. In addition to symmetrical parkinsonism, early falls, and non-reactivity dopaminomimetic therapy, the disease also manifests as swallowing problems with frequent choking incomprehensible, difficult speech. this paper, we present case patient PSP who exhibited severe speech disorders in clinical presentation Appropriate therapy was applied, resulting positive response partial relief mentioned symptoms. Case outline. A 68-year-old male referred therapist by neurologist due difficulties speaking. The impairments preparatory oral phases swallowing, including insufficient labial occlusion weakened tongue mobility. underwent intensive treatment for six months. rehabilitation program led improved function improvement Conclusion. patients should be approached seriously interdisciplinary, given absence causal reliance on symptomatic specific disabling conditions. It essential focus selection programs that can improve functions, well enhance quality life patients.

Язык: Английский

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Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 13, 2025

Abstract Background Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation microtubule-associated protein tau. Despite extensive research, mechanisms underlying diversity neuronal and glial tau pathology in different tauopathies are poorly understood. While there is growing understanding tauopathy-specific differences isoforms fibrillar structures, specific composition heterogenous lesions remains unknown. Here we study aggregates four major tauopathies: Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's (PiD), progressive supranuclear palsy (PSP). Methods We developed an approach for situ proximity labeling isolation aggregate-associated proteins using glass slides with formalin-fixed paraffin-embedded (FFPE) human postmortem brain tissue, termed Probe-dependent Proximity Profiling (ProPPr). used ProPPr analysis proteomes associated AT8-positive cellular from frontal cortices. Isolated were analyzed data-independent acquisition mass spectrometry. Co-immunofluorescence staining quantitative data selected tissue was performed to further investigate associations pathologies. Results Proteomics identified numerous common phospho-tau aggregates. Extensive validations candidates through immunofluorescence imaging distinct across cases demonstrate successful implementation unbiased discovery tissue. Our results reveal association retromer complex component vacuolar sorting-associated 35 (VPS35) lysosome-associated membrane glycoprotein 2 (LAMP2) types tauopathies. Furthermore, discovered disease-specific certain pathological lesions, including glycogen synthase kinase alpha (GSK3α), ferritin light chain (FTL), neuropeptide precursor VGF. Notably, identification FTL-positive microglia CBD astrocytic plaques indicate their potential role pathogenesis these lesions. Conclusions findings suitability FFPE local that provide valuable insights into proteomic landscape tauopathies, shedding on molecular pathology. This first comprehensive characterization tau-associated range enhances our heterogeneity mechanisms, informing strategies development diagnostic biomarkers targeted therapies.

Язык: Английский

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Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy

Immunobiology, Год журнала: 2025, Номер unknown, С. 152892 - 152892

Опубликована: Март 1, 2025

Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 polymorphic region with complex linkage patterns that has been implicated several autoimmune neurological disorders. HLA not systematically examined PSP. It unclear whether can interact to induce an mechanism. We evaluated autopsy confirmed PSP cohort (n = 44) compared allele/haplotype frequencies those of the reference group local deceased Canadian donor pool. performed HLA-Tau peptide binding prediction modelling Class II - Tau Peptide interactions. Odds ratio was 2.94 (95 % CI 1.01 8.55; p 0.047) for DQB1*06:01 allele, 2.59 1.39 4.83; 0.0025) narcolepsy-associated haplotype (DRB1*15:01-DQB1*06:02). One patient 4-repeat PSP-type pathology carrier IgLON5-associated (DRB1*10:01-DQB1*05:01). interactions revealed strong-binding peptides but PSP-protofilament fold alleles DQA1*01:02-DQB1*06:02 DQA1*01:03-DQB1*06:01. Our study suggests epitopes within may bind are found subset patients supporting notion pathophysiological component. These findings have implications subtyping stratifying therapies, including targeting immune modulation.

Язык: Английский

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