Role Of Tau Protein Research Articles

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

BackgroundAccumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer’s disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood.MethodsWe used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation.ResultsWe showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism.ConclusionOur results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

Role of Tau protein in long COVID and potential therapeutic targets.

Long COVID is an emerging public health burden and has been defined as a syndrome with common symptoms of fatigue, shortness of breath, cognitive dysfunction, and others impacting day-to-day life, fluctuating or relapsing over, occurring for at least two months in patients with a history of probable or confirmed SARS CoV-2 infection; usually three months from the onset of illness and cannot be explained by an alternate diagnosis. The actual prevalence of long-term COVID-19 is unknown, but it is believed that more than 17 million patients in Europe may have suffered from it during pandemic. Currently, there is limited understanding of the pathophysiology of this syndrome, and multiple hypotheses have been proposed. Our literature review has shown studies reporting tau deposits in tissue samples of the brain from autopsies of COVID-19 patients compared to the control group, and the in-vitro human brain organoid model has shown aberrant phosphorylation of tau protein in response to SARS-CoV-2 infection. Tauopathies, a group of neurodegenerative disorders with the salient features of tau deposits, can manifest different symptoms based on the anatomical region of brain involvement and have been shown to affect the peripheral nervous system as well and explained even in rat model studies. Long COVID has more than 203 symptoms, with predominant symptoms of fatigue, dyspnea, and cognitive dysfunction, which tauopathy-induced CNS and peripheral nervous system dysfunction can explain. There have been no studies up till now to reveal the pathophysiology of long COVID. Based on our literature review, aberrant tau phosphorylation is a promising hypothesis that can be explored in future studies. Therapeutic approaches for tauopathies have multidimensional aspects, including targeting post-translational modifications, tau aggregation, and tau clearance through the autophagy process with the help of lysosomes, which can be potential targets for developing therapeutic interventions for the long COVID. In addition, future studies can attempt to find the tau proteins in CSF and use those as biomarkers for the long COVID.

Memory, Sleep, and Tau Function.

Memory consolidation related to the hippocampal-cortex connection takes place during sleep. This connection may involve at least two steps- one in the NREM phase of sleep (transmission) and the other in the REM phase (consolidation). In this brief report, we comment on the role of tau protein in these two phases of sleep. The absence of tau decreases δ waves in NREM, whereas the overexpression of modified (phosphorylated and/or mutated) tau alters θ waves in REM.

Role of tau protein on the photophysical properties of fluorescent carbon dots

AbstractBackgroundGlobally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. However, tau protein undergoes post‐translational modifications like phosphorylation and aggregates causing cell death and spreading. In vitro, tau aggregation is typically evaluated using spectroscopic and microscopic methods.MethodsHerein, we propose to evaluate the use of carbon dots, an important type of fluorescent nanoparticles, as potential probes for tau protein aggregation. Dual fluorescent carbon dots were used in combination with tau protein, prior and post aggregation. Aggregation of the longest isoform of tau441 was induced using heparin. The fluorescence spectroscopy was used to analyze photophysical properties of carbon dots as a function of monomeric and aggregated tau.ResultsThe fluorescence quenching was observed for all protein containing samples, and was dependent on the aging time used for aggregation. The performance of carbon dots was compared to the standard Thioflavin T assay.ConclusionData indicate that nanomaterials may be useful platforms for sensing application targeting biomarkers of neurodegenerative diseases.

Role of Tau Protein on Photophysical Properties of Carbon Dots

Aggregation of intrinsically disordered Tau protein is a key biomarker of the progressive neurodegenerative disorder Alzheimer's Disease [1]. Although the precise mechanism by which tau aggregates is not well understood, abnormal post-translational modifications of tau have been implicated in the formation of tau aggregates and neurofibrillary tangles. In vitro, Tau aggregation may be detected by the fluorescent Thioflavin T dye, which is limited by non-specific interactions between the dye and other additives and low fluorescence quantum yield. CDs are a highly modifiable nanomaterials with characteristic optical properties and poorly-understood protein interactions. Using the novel fluorescent nanoallotrope, Carbon dots (CDs), we examined an alternative method for facile detection of intrinsically disordered Tau protein. Through photophysical studies of tau protein with two varieties of CDs, we determined that Tau protein decreased the fluorescent intensity of dual-fluorescing CDs to a greater extent than nitrogen-doped CDs after monitoring fluorescence. Tau protein aggregation was also induced by using heparin and this process was monitored by using ThT as well as CD assays. The CDs exhibited similar properties with heparin-aggregated tau samples and non-aggregated tau protein under specific experimental conditions. Data indicate that carbon dots are viable sensors for proteins and could be further optimized for disease biomarker detection and quantification in the development of rapid, sensitive and selective diagnostic assays.

Factors of Cell Degeneration or Death caused by Mutant Tau Protein

Tau protein is a microtubule associated protein mainly expressed in neurons. Under pathological conditions, Tau protein is abnormally hyperphosphorylated and separated from microtubules. Abnormal Tau aggregates form nerve fiber tangles, which are insoluble aggregates in the brain. It is due to the microtubule rupture caused by Tau protein dysfunction and it is associated with neurofibrillar degeneration in Alzheimer's disease.This paper studies several reports and research on the structure and function of Tau protein, the role of Tau protein in pathological diseases and its relationship with neurodegenerative diseases. This paper concludes that Tau protein has undergone abnormal modification and aggregation in many neurodegenerative diseases, but the specific type of Tau protein that causes neurotoxicity, as well as the pathogenesis of its phosphorylation and functional injury inducing nerve apoptosis, are still not fully understood. Various abnormal modifications of Tau protein occur under pathological conditions, and fatal cascade events occur at different stages of neuron apoptosis. Therefore, the causes and effects of cytotoxicity mediated by Tau protein are very complicated. Different or even opposite conclusions are sometimes drawn in Tau protein-mediated neurodegeneration studies. This may be due to differences in Tau protein type, gene mutation and protein expression level.

Protein-protein interactions in neurodegenerative diseases: A conspiracy theory.

Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.

Tau Protein and Its Role in Blood-Brain Barrier Dysfunction.

The blood–brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus. The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of the MAPT in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation. Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.

The role of tau-protein in the diagnosis of cognitive impairment in diabetes

The role of tau-protein in the diagnosis of cognitive impairment in diabetes

Role of Tau Protein in Alzheimer Disease and its Inhibitors from Plants

Alzheimer is a common neurodegenerative disease that affects 45 million people worldwide. Pathogenesis usually begins with formation of plaques and neurofibrillary tangles due to abnormal folding of amyloid beta and tau proteins. Tau proteins are important member of microtubule associated proteins and involved in constitution of microtubules network in neurons which play major role in progression of Alzheimer disease. Hyper phosphorylation and aggregation of Tau protein on chromosome 17 may be the sign of several neurodegenerative pathologies like Alzheimer disease (AD), Parkinsonism, fronto-temporal dementia and Pick disease. The complete cure of AD is not possible be with already marketed drugs. From this review article it is concluded that Tau protein is an important biomarker of Alzheimer disease. Usage of extracts from various plants i.e Danggui Longhui Wang, Hymenialdisine, Morin, Salvia officinalis, Ginseng, helps in effective treatment of disease and hence a step forward to reduce the prevalence of Alzheimer disease.

The Role of Tau Protein in Diseases

The Role of Tau Protein in Diseases

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 Tau variants for their ability to be seeded by exogenous Tau fibrils. Our findings revealed stark differences between FTDP-17 Tau variants in their ability to be seeded, with variants at Pro301 and Ser320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain Tau protein regions and unique residues, including the role of Pro301 in inhibiting Tau aggregation. We also revealed potential barriers in cross-seeding between three-repeat and four-repeat Tau isoforms. Overall, these differences alluded to potential mechanistic differences between wildtype and FTDP-17 Tau variants, as well as different Tau isoforms, in influencing Tau aggregation. Furthermore, by combining two FTDP-17 Tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that do not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate Tau aggregation without the need for exogenous Tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate Tau aggregation.

A Comprehensive Review on the Role of Tau Proteins in Alzheimer's Pathology

Tau proteins are the one of the most important causes of neurological diseases like Alzheimer's disease (AD). Tau proteins are the stabilized form of microtubule associated protein (MAP) of a normal motor neuron. Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of the tau's main functions is to modulate the stability of axonal microtubules. Neurofibrillary tangles are obtained by hyperphosphorylation of a microtubule associated protein. This article deals with the role of Tau proteins and the methods in which they lead to AD

Tau Protein, Ischemic Injury and Vascular Dementia

Clinical, neuroimaging and neuropathological studies have confirmed overlap between Alzheimer's disease (AD) and vascular dementia (VaD). Classical neuropathological changes of AD (plaques and tangles) can be present in VaD. We review neuroimaging, biochemical and animal studies to consider the role of tau protein in ischemic injury and VaD pathogenesis. The evidence comes largely from transgenic animal studies that confirm that tau transgenes influence cerebral vasculature. Clinicobiochemical studies in the cerebrospinal fluid (CSF) have, similarly, confirmed alterations in both total and phosphorylated tau protein in VaD. These data suggest that tau protein not only serves as a potential diagnostic tool for differential diagnosis of VaD from other types of dementia, but may also be a therapeutic target in ischemic stroke.

Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer's disease

This review addresses the current hypotheses of the pathogenesis of Alzheimer's disease (AD) and methods of its pharmacological corrections. The following topics are reviewed: a role of ß-amyloid in the pathogenesis of AD, a role of tau-protein in the pathogenesis of AD, main hypotheses of the pathogenesis, the relationship between ß-amyloid and tau-protein, the dysfunction of synapses in AD, a neuroimmune hypothesis, treatment approaches.

107. CSF levels of tau protein are related to detrimental SLAI and LTP-like cortical plasticity in AD patients

AD patients are characterized by an impairment of Long Term Potentiation (LTP)-like cortical plasticity. AD patients have a weakened Short Latency Afferent Inhibition (SLAI), a neurophysiological measure under cholinergic control. It’s been proposed that high levels of T-tau in AD patients CSF are related to a faster cognitive decline and more malignant form of dementia. Aim of this study is to investigate the relation between CSF values of beta-amyloid, T-tau and P-tau and cortical plasticity in a sample of AD patients. By means of repetitive transcranial magnetic stimulation we tested in 55 AD patients the LTP/LTD-like effects induced by the intermittent TBS (iTBS) and continuous TBS (cTBS) protocols, and the efficacy of SLAI circuits. K-means cluster analysis including the 3 CSF biomarkers was performed.The three resulting clusters differed by the value of T-tau: cluster 1 (low levels); cluster 2 (intermediate levels); cluster 3 (high levels). Cluster 2 showed more impaired LTP-like cortical plasticity and SLAI efficiency, while cluster 1 and cluster 3 have surprisingly the same pathological trends. Our results shed light on the role of tau protein in the physiopathology of AD, showing a similar U shaped-curve related to the level of LTP impairment and SLAI deficiency.

The role of tau protein in HIV-associated neurocognitive disorders.

Given the increased life expectancy of human immunodeficiency virus (HIV) infected individuals treated with combination antiretroviral therapy (cART) and the ongoing inflammation observed in the brains of these patients, it is likely that premature neurodegeneration as measured by phospho-tau (p-tau) or increased total tau (t-tau) protein may become an increasing problem. This review examines the seven human studies that have occurred over the past 14 years measuring p-tau and/or t-tau in cerebrospinal fluid (CSF) or via post-mortem brain immunohistochemistry. Although not all studies are in agreement as to the changes in p-and t-tau in HIV infected patients, HIV persists in the brain despite cART. Thus is it is suggested that those maintained on long-term cART may develop tau pathology beyond the extent seen in the studies reviewed herein and overtime may then reach the threshold for clinical manifestation.

MAPT gene rs1052553 variant is not associated with the risk for multiple sclerosis

Background/ObjectivesSome experimental data suggest a possible role of tau protein in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. The aim of this study was to investigate a possible influence of the SNP rs1052553 in the MAPT gene in the risk for relapsing bout onset (relapsing–remitting and secondary progressive) MS. MethodsWe analyzed the allelic and genotype frequency of MAPT rs1052553, which has been associated with some neurodegenerative diseases, in 259 patients with relapsing bout onset MS and 291 healthy controls, using TaqMan Assays. ResultsMAPT rs1052553 allelic and genotype frequencies did not differ significantly between relapsing bout onset MS patients and controls, and were unrelated with the age of onset of MS or gender. ConclusionsThese results suggest that MAPT rs1052553 polymorphism is not related with the risk for relapsing bout onset MS.

The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD.

Tau protein: a possible prognostic factor in optic neuritis and multiple sclerosis

Background: Tau protein has been proposed as biomarker of axonal damage leading to irreversible neurological impairment in MS. CSF concentrations may be useful when determining risk of progression from ON to MS. Objective: To investigate the association between tau protein concentration and 14-3-3 protein in the cerebrospinal fluid (CSF) of patients with monosymptomatic optic neuritis (ON) versus patients with monosymptomatic onset who progressed to multiple sclerosis (MS). To evaluate results against data found in a complete literature review. Methods: A total of 66 patients with MS and/or ON from the Department of Neurology of Glostrup Hospital, University of Copenhagen, Denmark, were included. CSF samples were analysed for tau protein and 14-3-3 protein, and clinical and paraclinical information was obtained from medical records. Results: The study shows a significantly increased concentration of tau protein in CSF from patients with relapsing–remitting MS and patients monosymptomatic at onset who progressed to MS, but interestingly no increased tau protein concentration in monosymptomatic ON. The concentration of tau protein was significantly correlated to Expanded Disability Status Scale score. No 14-3-3 protein was detected in any CSF sample. Conclusions: The results of this study invite further exploration of the possible role of tau protein as a prognostic factor to predict progression from ON to MS in future studies.