Probing Flow-Induced Biomolecular Interactions With Micro-Extensional Rheology: Tau Protein Aggregation

2020 ◽  
Vol 142 (3) ◽  
Author(s):  
H. Hosseini ◽  
A. Rangchian ◽  
M. L. Prins ◽  
C. C. Giza ◽  
J. W. Ruberti ◽  
...  
Keyword(s):  
Tau Protein ◽  
Chronic Traumatic Encephalopathy ◽  
Extensional Flow ◽  
Protein Structures ◽  
Small Sample ◽  
Protein Solutions ◽  
Rheological Method ◽  
Extensional Strain ◽  
Protein Isoform ◽  
Induced Aggregation

Abstract Biomolecules in solutions subjected to extensional strain can form aggregates, which may be important for our understanding of pathologies involving insoluble protein structures where mechanical forces are thought to be causative (e.g., tau fibers in chronic traumatic encephalopathy (CTE)). To examine the behavior of biomolecules in solution under mechanical strains requires applying rheological methods, often to very small sample volumes. There were two primary objectives in this investigation: (1) To probe flow-induced aggregation of proteins in microliter-sized samples and (2) To test the hypothesis that tau protein aggregates under extensional flow. Tau protein (isoform:3R 0 N; 36.7 kDa) was divided into 10 μl droplets and subjected to extensional strain in a modified tensiometer. Sixteen independent tests were performed where one test on a single droplet comprised three extensional events. To assess the rheological performance of the fluid/tau mixture, the diameter of the filament that formed during extension was tracked as function of time and analyzed for signs of aggregation (i.e., increased relaxation time). The results were compared to two molecules of similar and greater size (Polyethylene Oxide: PEO35, 35 kDa and PEO100, 100 kDa). Analysis showed that the tau protein solution and PEO35 are likely to have formed aggregates, albeit at relatively high extensional strain rates (∼10 kHz). The investigation demonstrates an extensional rheological method capable of determining the properties of protein solutions in μl volumes and that tau protein can aggregate when exposed to a single extensional strain with potentially significant biological implications.

scholarly journals A Mechanism for the Development of Chronic Traumatic Encephalopathy From Persistent Traumatic Brain Injury

2019 ◽  
Vol 13 ◽  
pp. 117906951984993 ◽  
Author(s):  
Melissa Demock ◽  
Steven Kornguth
Keyword(s):  
Traumatic Brain Injury ◽  
Amino Acid ◽  
Brain Injury ◽  
Tau Protein ◽  
Chronic Traumatic Encephalopathy ◽  
Hla Class I ◽  
Class I ◽  
Cross Linking ◽  
Neural Cells ◽  
The Cross

A mechanism that describes the progression of traumatic brain injury (TBI) to end-stage chronic traumatic encephalopathy (CTE) is offered in this article. This mechanism is based upon the observed increase in the concentration of both tau protein and of human leukocyte antigen (HLA) class I proteins; the HLA increase is expressed on the cell membrane of neural cells. These events follow the inflammatory responses caused by the repetitive TBI. Associated inflammatory changes include macrophage entry into the brain parenchyma from increased permeability of the blood-brain barrier (BBB) and microglial activation at the base of the sulci. The release of interferon gamma from the microglia and macrophages induces the marked increased expression of HLA class I proteins by the neural cells and subsequent redistribution of the tau proteins to the glial and neuronal surface. In those individuals with highly expressed HLA class I C, the high level of HLA binds tau protein electrostatically. The ionic region of HLA class I C (amino acid positions 50-90) binds to the oppositely charged ionic region of tau (amino acid positions 93-133). These interactions thereby shift the cellular localization of the tau and orient the tau spatially so that the cross-linking sites of tau (275-280 and 306-311) are aligned. This alignment facilitates the cross-linking of tau to form the intracellular and extracellular microfibrils of tau, the primary physiological characteristic of tauopathy. Following endocytosis of the membrane HLA/tau complex, these microfibrils accumulate and produce a tau-storage-like disease. Therefore, tauopathy is the secondary collateral process of brain injury, resulting from the substantial increase in tau and HLA expression on neural cells. This proposed mechanism suggests several potential targets for mitigating the clinical progression of TBI to CTE.

Flavonoids Inhibit Heparin-Induced Aggregation of the Third Repeat (R3) of Microtubule-Binding Domain of Alzheimer’s Tau Protein

2010 ◽  
Vol 83 (8) ◽  
pp. 911-922 ◽  
Author(s):  
Lin-Jie Han ◽  
Shuo Shi ◽  
Leng-Feng Zheng ◽  
Dan-Jing Yang ◽  
Tian-Ming Yao ◽  
...  
Keyword(s):  
Tau Protein ◽  
Binding Domain ◽  
Microtubule Binding ◽  
The Third ◽  
Microtubule Binding Domain ◽  
Induced Aggregation

scholarly journals Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

2019 ◽  
Author(s):  
Hamad Yadikar ◽  
Isabel Torres ◽  
Gabrielle Aiello ◽  
Milin Kurup ◽  
Zhihui Yang ◽  
...  
Keyword(s):  
Tau Protein ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Traumatic Encephalopathy ◽  
Cortical Cell ◽  
Protein Kinase Inhibitors ◽  
Tau Hyperphosphorylation ◽  
Drug Candidates ◽  
A Cell ◽  
Cortical Cell Cultures

ABSTRACTTauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed conflicting results between the two neuronal cultures.This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.

scholarly journals High Energy Radiation-Induced Aggregation of Plasma Proteins. Time Resolved Light Scattering Measurements

1980 ◽  
Vol 35 (2) ◽  
pp. 217-220 ◽  
Author(s):  
H. Kihara ◽  
W. Schnabel
Keyword(s):  
High Energy ◽  
Relative Increase ◽  
Protein Solutions ◽  
Oh Radicals ◽  
Time Resolved ◽  
Short Pulses ◽  
Radiation Chemical ◽  
Protein Molecules ◽  
Radiation Induced ◽  
Induced Aggregation

Abstract Human immunoglobulin (IgG), bovine fibrinogen and bovine serum albumin were irradiated at room temperature with short pulses (50 ns to 2 μs) of 16 MeV electrons in 0.2 M NaClO4 solution containing phosphate buffer (pH 7.5). In the presence of N2O the intensity of light (LSI) scattered by the protein solutions increased after the pulse indicating aggregation. The latter process originates from the attack of protein molecules by OH radicals (aggregation is impeded by t-butanol and augmented by N2O). Upon plotting the relative increase of LSI vs. log time (after the pulse) sigmoidally shaped curves were obtained.From these findings and results of optical absorption measurements the following is inferred: Aggregation occurs as a consequence of chemical alterations of the protein molecules induced by the attack by OH radicals. The transient species formed during and a few pis after the pulse are reacting within a period of several ms. At the end of this period the formation of aggregates starts. It is concluded that the primary radiation chemical process consists (among others) in the generation of nuclcation sites. The latter subsequently initiate aggregation processes.

Preservation of native conformation during aluminium-induced aggregation of tau protein

Neuroreport ◽  
1996 ◽  
Vol 7 (5) ◽  
pp. 1072-1076 ◽  
Author(s):  
T. R. Madhav ◽  
S. Vatsala ◽  
T. Ramakrishna ◽  
J. Ramesh ◽  
K. R. K. Easwaran
Keyword(s):  
Tau Protein ◽  
Native Conformation ◽  
Induced Aggregation

Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms

2020 ◽  
Vol 40 (04) ◽  
pp. 430-438 ◽  
Author(s):  
Jonathan D. Cherry ◽  
Katharine J. Babcock ◽  
Lee E. Goldstein
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Chronic Traumatic Encephalopathy ◽  
Biomechanical Properties ◽  
Ice Hockey ◽  
American Football ◽  
Head Impacts ◽  
Blast Exposure ◽  
Hyperphosphorylated Tau Protein ◽  
The Brain

AbstractExposure to repetitive neurotrauma increases lifetime risk for developing progressive cognitive deficits, neurobehavioral abnormalities, and chronic traumatic encephalopathy (CTE). CTE is a tau protein neurodegenerative disease first identified in boxers and recently described in athletes participating in other contact sports (notably American football, ice hockey, rugby, and wrestling) and in military veterans with blast exposure. Currently, CTE can only be diagnosed by neuropathological examination of the brain after death. The defining diagnostic lesion of CTE consists of patchy perivascular accumulations of hyperphosphorylated tau protein that localize in the sulcal depths of the cerebral cortex. Neuronal abnormalities, axonopathy, neurovascular dysfunction, and neuroinflammation are triggered by repetitive head impacts (RHIs) and likely act as catalysts for CTE pathogenesis and progression. However, the specific mechanisms that link RHI to CTE are unknown. This review will explore two important areas of CTE pathobiology. First, we will review what is known about the biomechanical properties of RHI that initiate CTE-related pathologies. Second, we will provide an overview of key features of CTE neuropathology and how these contribute to abnormal tau hyperphosphorylation, accumulation, and spread.

scholarly journals Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Adam D. Bachstetter ◽  
Filip G. Garrett ◽  
Gregory A. Jicha ◽  
Peter T. Nelson
Keyword(s):  
Brain Injury ◽  
Literature Review ◽  
Tau Protein ◽  
Chronic Traumatic Encephalopathy ◽  
Later Life ◽  
Arachnoid Cysts ◽  
Phosphorylated Tau ◽  
Pathologic Features ◽  
Tau Aggregation ◽  
Phosphorylated Tau Protein

AbstractAstrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age—affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (> 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects’ left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma.

scholarly journals Chronic traumatic encephalopathy – current state of knowledge

2021 ◽  
Vol 11 (8) ◽  
pp. 86-100
Author(s):  
Łukasz Bryliński ◽  
Paulina Drożak ◽  
Martyna Drożak ◽  
Katarzyna Augustowska ◽  
Piotr Duda ◽  
...  
Keyword(s):  
Tau Protein ◽  
Behavioral Problems ◽  
Current Knowledge ◽  
Chronic Traumatic Encephalopathy ◽  
Imaging Techniques ◽  
Head Injuries ◽  
Memory Loss ◽  
Ice Hockey ◽  
Diagnostic Methods ◽  
American Football

Introduction and purpose. Chronic traumatic encephalopathy (CTE) is a tauopathy caused by repetitive, mild head injuries. It is characterized by perivascular accumulation of hyperphosphorylated tau protein in the neurons and astrocytes. CTE leads to changes in central nervous system, both on microscopic and macroscopic level. The aim of the study was to present the current knowledge on chronic traumatic encephalopathy among athletes, its predisposing factors, symptoms and consequences, as well as diagnostic methods and treatment.Description. CTE occurs among contact sport players, such as American football, ice hockey, soccer, baseball, box and MMA (mixed martial arts), as well as among soldiers and victims of domestic violence. Repetitive head injuries and long career duration increase the risk of CTE. Symptoms of chronic traumatic encephalopathy include a commonly occurring triad: cognitive disturbances, behavioral problems and mood disturbances. Other symptoms include memory loss, parkinsonism, headaches, speech and walking problems. Currently, the only diagnostic method of CTE is a posthumous detection of neuropathological markers. Methods such as detection of exosomal tau protein in plasma and imaging techniques give hope to diagnose CTE in alive patients. Treatment methods of CTE, such as LIPUS (low intensity pulsed ultrasound) therapy are currently being developed.Conclusions. Chronic traumatic encephalopathy among athletes is a serious problem that affects multiple people due to the popularity of contact sports. Thus, an emphasis should be put on prevention, raising awareness and appropriate protection of athletes through changes in regulations and improvement of protective equipment.

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