The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases DOI Open Access
Seojin Lee, Gábor G. Kovács

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4269 - 4269

Published: April 12, 2024

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports contribution iron disease pathologies, but delineation its pathogenic role yet challenged by complex multiple neurotoxicity mechanisms supporting reciprocal influence between protein pathology. Here, we review major proteinopathy-specific observations four distinct hypotheses: (1) deposition consequence pathology; (2) promotes (3) protects from or hinders (4) pathology contribute parallelly to pathogenesis. an essential element for physiological function, requiring fine balance levels. Understanding disease-related at more intricate systemic level critical advancements chelation therapies.

Language: Английский

Structure-based classification of tauopathies DOI
Yang Shi, Wenjuan Zhang, Yang Yang

et al.

Nature, Journal Year: 2021, Volume and Issue: 598(7880), P. 359 - 363

Published: Sept. 29, 2021

Language: Английский

Citations

611
Tauopathies: new perspectives and challenges DOI Creative Commons
Yi Zhang, Kaimin Wu, Yang Liu

et al.

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

Citations

187
Cellular and pathological heterogeneity of primary tauopathies DOI Creative Commons
Dah‐eun Chloe Chung, Shanu F. Roemer, Leonard Petrucelli

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 23, 2021

Abstract Microtubule-associated protein tau is abnormally aggregated in neuronal and glial cells a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested pathological species may act seed promotes aggregation endogenous naïve contributes propagation pathology. While they share common feature, tauopathies distinct from one another with respect predominant isoforms accumulate the selective vulnerability brain regions cell types inclusions. For instance, primary present pathology, while it mostly Alzheimer’s disease (AD). Also, morphologies inclusions can greatly vary even within same type, suggesting mechanisms or conformers each tauopathy. Neuropathological heterogeneity across challenges our understanding pathophysiology behind seeding aggregation, well efforts develop effective therapeutic strategies for AD other In this review, we describe diverse neuropathological features discuss what has been learned experimental mouse models, advanced transcriptomics, cryo-electron microscopy (cryo-EM) on biology underlying type-specific

Language: Английский

Citations

138
The role of noradrenaline in cognition and cognitive disorders DOI Creative Commons
Negin Holland, Trevor W. Robbins, James B. Rowe

et al.

Brain, Journal Year: 2021, Volume and Issue: 144(8), P. 2243 - 2256

Published: March 11, 2021

Abstract Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from locus coeruleus, acting through alpha beta adrenoreceptors. Loss these is common in neurodegenerative diseases contributes their cognitive behavioural deficits. We review evidence for a modulation its contribution Alzheimer’s disease, Parkinson’s disease other disorders. discuss advances human imaging computational methods that quantify coeruleus function humans, highlight potential new treatment strategies.

Language: Английский

Citations

132
Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy DOI Creative Commons
Shanu F. Roemer, Lea T. Grinberg, John F. Crary

et al.

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(4), P. 603 - 614

Published: Aug. 10, 2022

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 based on the presence neurofibrillary tangles basal ganglia brainstem. These did not stipulate detection methods or incorporate glial tau pathology. In this study, 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin eosin (H&E) phosphorylated (AT8) immunohistochemistry. The cases included 15 typical atypical PSP other tauopathies. Blinded to clinical neuropathological information, raters provided categorical diagnosis (PSP not-PSP) upon provisional that required pretangles two three (substantia nigra, subthalamic nucleus, globus pallidus) tufted astrocytes one (peri-Rolandic cortices, putamen). showed high sensitivity (0.97) specificity (0.91), as well almost perfect inter-rater reliability diagnosing differentiating it tauopathies (Fleiss kappa 0.826). Most (17/25) had 100% agreement across all raters. Rainwater Charitable Foundation neuropathologic feature simplified diagnostic algorithm immunohistochemistry an essential feature.

Language: Английский

Citations

77
Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model DOI Creative Commons
Christopher Käufer,

Cara Sophie Schreiber,

Anna-Sophia Hartke

et al.

EBioMedicine, Journal Year: 2022, Volume and Issue: 79, P. 103999 - 103999

Published: April 16, 2022

Neurological symptoms such as cognitive decline and depression contribute substantially to post-COVID-19 syndrome, defined lasting several weeks after initial SARS-CoV-2 infection. The pathogenesis is still elusive, which hampers appropriate treatment. Neuroinflammatory responses neurodegenerative processes may occur in absence of overt neuroinvasion.Here we determined whether intranasal infection male female syrian golden hamsters results persistent brain pathology. Brains 3 (symptomatic) or 14 days (viral clearance) post versus mock (n = 10 each) were immunohistochemically analyzed for viral protein, neuroinflammatory response accumulation tau, hyperphosphorylated tau alpha-synuclein protein.Viral protein the nasal cavity led pronounced microglia activation olfactory bulb beyond clearance. Cortical but not hippocampal neurons accumulated alpha-synuclein, inflammation neurodegeneration. Importantly, all regions affected, line with selective vulnerability.Thus, despite virus brain, develop signatures proteinopathies that progressive neuronal dysfunction. Further depth analysis this important mechanism required.Federal Ministry Health (BMG; ZMV I 1-2520COR501), Federal Education Research (BMBF 01KI1723G), Science Culture Lower Saxony Germany (14 - 76103-184 CORONA-15/20), German Foundation (DFG; 398066876/GRK 2485/1), Luxemburgish National Fund (FNR, Project Reference: 15686728, EU SC1-PHE-CORONAVIRUS-2020 MANCO, no > 101003651).

Language: Английский

Citations

75
Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases DOI
Dan Li, Cong Liu

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(9), P. 523 - 534

Published: May 30, 2022

Language: Английский

Citations

75
Tau deposition patterns are associated with functional connectivity in primary tauopathies DOI Creative Commons
Nicolai Franzmeier, Matthias Brendel, Leonie Beyer

et al.

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

Citations

72
Cellular and pathological functions of tau DOI
C Bravo, Sarah Naguib, Li Gan

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

Citations

36
Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden DOI Creative Commons

Giuseppe Mario Bentivenga,

Angela Mammana, Simone Baiardi

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Jan. 19, 2024

Abstract The development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein (αSyn) cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance early pathological stages or low (LB) pathology load only been assessed small cohorts. Moreover, the relationship between kinetic parameters, number brain seeds LB burden by immunohistochemistry never systematically investigated. We tested 269 antemortem CSF samples 138 serially diluted homogenates from patients with without neuropathological evidence LBD different Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. we looked consecutive series 604 Creutzfeldt–Jakob (CJD)-affected brains. RT-QuIC showed 100% sensitivity limbic neocortical stages. assay was significantly lower (37.5% Braak 1 2, 73.3% 3) focal (50% amygdala-predominant). average positive replicates correlated stage. Brain homogenate higher than detection αSyn. In latter, parameter lag phase (time to reach threshold) strongly concentration serial dilution experiments. Finally, incidental prevalence 8% CJD cohort. present results indicate that (a) high specificity sufficient detect all at > 3 most those stage 3; (b) deposition precedes formation neurites; (c) provides “quantitative” information regarding burden, being promising variables be used clinical setting.

Language: Английский

Citations

35