scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

2018 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G. Murzin ◽  
Juan Fan ◽  
R. Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Microtubule Binding ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
Negative Stain ◽  
Different Types ◽  
Filamentous Inclusions

AbstractThe assembly of microtubule-associated protein tau into abundant filamentous inclusions underlies a range of neurodegenerative diseases. The finding that tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases raises the question of what kinds of structures of tau filaments form in vitro. Here, we used electron cryo-microscopy (cryo-EM) and negative-stain immuno-gold electron microscopy (immuno-EM) to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 4R tau assembles into at least four different types of filaments. Cryo-EM structures of three types of 4R filaments reveal similar “kinked hairpin” folds, in which the second and third repeats pack against each other. 3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack against each other in a parallel, yet asymmetric, manner. None of the heparin-induced tau filaments resemble those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results indicate that tau filaments are structurally versatile, and raise questions about the relevance of in vitro assembled amyloids.

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G Murzin ◽  
Juan Fan ◽  
R Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
In Vitro Assembly ◽  
Immuno Electron Microscopy ◽  
Structural Versatility ◽  
Filamentous Inclusions

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.

scholarly journals From genetics to pathology: tau and a–synuclein assemblies in neurodegenerative diseases

2001 ◽  
Vol 356 (1406) ◽  
pp. 213-227 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini ◽  
Louise C. Serpell ◽  
John Berriman ◽  
Michael J. Smith ◽  
...  
Keyword(s):  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Tau Protein ◽  
Nerve Cells ◽  
Degenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Filamentous Inclusions

The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule–associated protein tau or the protein α–synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the α–synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and α–synuclein can cause neurodegeneration.

scholarly journals Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases

2021 ◽  
Vol 13 ◽  
Author(s):  
Rodrigo Diaz-Espinoza
Keyword(s):  
Electron Microscopy ◽  
High Resolution ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Solid State Nmr ◽  
Molecular Level ◽  
Molecular Targets ◽  
Protein Tau ◽  
Isolation Methods

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aβ) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD. Tau and α-Sn aggregates are also present in other neurodegenerative diseases. The insoluble nature and heterogeneity of amyloids have hampered their study at the molecular level. However, the use of solid state NMR and Cryogenic-electron microscopy along with fine-tuned modulation of the aggregation in vitro and improved isolation methods of brain-derived amyloids has allowed the elucidation of these elusive conformations at high resolution. In this work, we review the latest progress on the recent amyloid structures reported for Aβ, Tau, and α-Sn. The two-fold symmetry emerges as a convergent feature in the tridimensional arrangement of the protofilaments in the fibrillary structure of these pathological amyloids, with many of them exhibiting a Greek-key topology as part of their overall architecture. These specific features can serve as novel guides to seek potential molecular targets in drug design efforts.

Studies on Thrombolysis with Streptokinase

1971 ◽  
Vol 25 (02) ◽  
pp. 354-378 ◽  
Author(s):  
R Gottlob ◽  
L Stockinger ◽  
U Pötting ◽  
G Schattenmann
Keyword(s):  
Electron Microscopy ◽  
Cross Section ◽  
Whole Blood ◽  
Jugular Vein ◽  
Thin Sections ◽  
The Third ◽  
Morphological Findings ◽  
Blood Clots ◽  
Arteries And Veins

SummaryIn vitro whole blood clots of various ages, experimental thrombi produced in the jugular vein of rabbits and human thrombi from arteries and veins were examined in semi-thin sections and by means of electron microscopy.In all types of clots examined a typical course of retraction was found. Retraction starts with a dense excentrical focus which grows into a densification ring. After 24 hours the entire clot becomes almost homogeneously dense; later a secondary swelling sets in.Shortly after coagulation the erythrocytes on the rim of the clot are bi-concave discs. They then assume the shape of crenate spheres, turn into smooth spheres and finally become indented ghosts which have lost the largest part of their contents. In the inner zone, which makes up the bulk of the clot, we observed bi-concave discs prior to retraction. After retraction we see no crenations but irregularly shaped erythrocytes. Once the secondary swelling sets in, the cross-section becomes polygonal and later spherical. After extensive hemolysis we observe the “retiform thrombus” made up of ghosts.Experimental and clinical thrombi present the same morphology but are differentiated from in vitro clots by: earlier hemolysis, immigration of leukocytes, formation of a rim layer consisting of fibrin and thrombocytes, and the symptoms of organization. Such symptoms of organization which definitely will prevent lysis with streptokinase were found relatively late in experimental and clinical thrombi. Capillary buds and capillary loops were never found in clinical thrombi prior to the third month.The morphological findings agree with earlier physical and enzymatic investigations. The observation that phenomena of reorganization occur relatively late and frequently only in the rim areas of large thrombi explains why lytic therapy is possible in some of the chronic obliterations.

scholarly journals In VitroAdherence of Oral Bacteria to Different Types of Tongue Piercings

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Lucas Pereira Borges ◽  
Julio Cesar Campos Ferreira-Filho ◽  
Julia Medeiros Martins ◽  
Caroline Vieira Alves ◽  
Bianca Marques Santiago ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Bacterial Adhesion ◽  
Oral Bacteria ◽  
The Other ◽  
Control Group ◽  
Colony Forming Units ◽  
Different Types ◽  
Scanning Electron

The purpose of this work was to verifyin vitroadherence ofE. corrodensandS. oralisto the surface of tongue piercings made of surgical steel, titanium, Bioplast, and Teflon. For this, 160 piercings were used for the count of Colony Forming Units (CFU) and 32 piercings for analysis under scanning electron microscopy. Of these, 96 (24 of each type) were individually incubated in 5 mL of BHI broth and 50 μL of inoculum at 37°C/24 h. The other 96 piercings formed the control group and were individually incubated in 5 mL of BHI broth at 37°C/24 h. Plates were incubated at 37°C/48 h for counting of CFU/mL and data were submitted to statistical analysis (pvalue<0.05). ForE. corrodens, difference among types of material was observed (p<0.001) and titanium and surgical steel showed lower bacterial adherence. The adherence ofS. oralisdiffered among piercings, showing lower colonization (p<0.007) in titanium and surgical steel piercings. The four types of piercings were susceptible to colonization byE. corrodensandS. oralis, and bacterial adhesion was more significant in those made of Bioplast and Teflon. The piercings presented bacterial colonies on their surface, being higher in plastic piercings probably due to their uneven and rough surface.

scholarly journals Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

2021 ◽  
Author(s):  
Maria Grazia Spillantini ◽  
Jack H Brelstaff ◽  
Matthew Mason ◽  
Taxiarchis Katsinelos ◽  
William A McEwan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neurodegenerative Diseases ◽  
Matrix Remodeling ◽  
Matrix Metalloprotease ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Senescent Phenotype ◽  
Human Brains ◽  
Tau Aggregate

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

scholarly journals Phase separation of proSAAS into spheres results in core sequestration of TDP-43216-414 aggregates

2020 ◽  
Author(s):  
Juan R. Peinado ◽  
Kriti Chaplot ◽  
Timothy S. Jarvela ◽  
Edward Barbieri ◽  
James Shorter ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Phase Separation ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Model System ◽  
Chaperone Activity ◽  
Chaperone Proteins ◽  
Cytotoxic Effects ◽  
Vital Functions

SUMMARYChaperone proteins perform vital functions in the maintenance of cellular proteostasis and play important roles during the development of neurodegenerative diseases involving protein aggregation. We have previously reported that a secreted neuronal chaperone known as proSAAS exhibits potent chaperone activity in vitro against protein aggregation and blocks the cytotoxic effects of amyloid and α-synuclein oligomers. Here we report that overexpression of proSAAS generates dense, membraneless 2 μm spheres which can increase by fusion up to 4 μM during expression within the cytoplasm. The presence of dense proSAAS spheres was confirmed using electron microscopy. ProSAAS spheres selectively sequestered GFP-TDP-43216-414 within their cores, resulting in cellular redistribution and retardation of degradation. ProSAAS expression was protective against TDP-43 cytotoxicity in a yeast model system. Aggregate sequestration via proSAAS encapsulation may provide protection from cell-to-cell transmission of aggregates and explain the as-yet unclear mechanism underlying the cytoprotective chaperone action of proSAAS.

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