Cerebrospinal fluid (CSF) concentrations of total Tau and Tau phosphorylated at threonine (position 181 [pTau181]) were studied with ELISA in a group of carefully selected patients with a neurochemically supported diagnosis of Alzheimers disease (AD, n=9; age range, 51-89 yr) and in a group of sex- and age-matched nondemented controls (n=9; age range, 52-81 yr). The concentration of both biomarkers is increased significantly in the AD group (total Tau, p,0.0008; pTau181, p,0.008). A significant correlation between CSF concentrations of both biomarkers is observed (R=0.897; p,0.001). Neither total Tau nor pTau181 correlates with age or degree of memory impairment, and only a tendency is observed between the concentrations of total Tau and Aβ42 in the CSF. Our results further confirm a possible role of pTau181 as a diagnostic tool in AD. The current literature regarding the physiological and pathological role of phosphorylated Tau proteins is reviewed, as well as the role of these proteins as ...
We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology of Alzheimers disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ...
Title:Optimized Turmeric Extract Reduces β-Amyloid and Phosphorylated Tau Protein Burden in Alzheimers Transgenic Mice. VOLUME: 9 ISSUE: 4. Author(s): R. Douglas Shytle, Jun Tan, Paula C. Bickford, Kavon Rezai-zadeh, L Hou, Jin Zeng, Paul R. Sanberg, Cyndy D. Sanberg, Randall S. Alberte, Ryan C. Fink and Bill Roschek Jr. Affiliation:HerbalScience Group LLC., Naples, FL 34110, USA.. Keywords: Alzheimers disease, Tau phosphorylation, turmeric, curcuminoids, Aß cascade hypothesis, chronic inflammation Abstract:In a previous in vitro study, the standardized turmeric extract, HSS-888, showed strong inhibition of Aβ aggregation and secretion in vitro, indicating that HSS-888 might be therapeutically important. Therefore, in the present study, HSS-888 was evaluated in vivo using transgenic Alzheimer mice (Tg2576) over-expressing Aβ protein. Following a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of ...
Accumulation of A beta peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimers disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic A beta peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by beta-secretase and gamma-secretase inhibition, as well as gamma-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular A beta signaling to ...
Tau is a microtubule stabilizing protein that forms aggregates in Alzheimers disease (AD). Tau derived from AD patients brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models. Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential. CSF was injected intrahippocampally into young P301S tau transgenic mice. CSF obtained from AD or MCI patients increased hippocampal tau hyperphosphorylation and tau tangle formation in these mice at 4 months post-seeding. Tau pathology was also accentuated in the contralateral hippocampus, and in anterior and posterior directions, indicative of spreading. We provide first evidence for in vivo prion-like properties of AD patients CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD.
The abnormal phosphorylation of tau protein at serine 202 in Alzheimers disease recapitulates phosphorylation during development ...
We measured tau concentrations in cerebrospinal fluid (CSF) samples taken during the lifetime of 43 patients with Alzheimers disease (AD) and correlated these values with neurofibrillary tangle (NFT) scores as well as glial fibrillary acidic protein (GFAP) expression as a marker of astrocytosis in the brain post-mortem. The CSF tau values showed a positive correlation with neocortical NFT scores (r = 0.44, p | 0.005), while GFAP immmunoreactivity did not correlate with CSF tau. This study reveals a high variation in CSF tau values in patients with neuropathologically confirmed AD (range 194-1539 pg/ml) and indicates that high CSF tau values in the late phase of Alzheimers disease predict severe neurodegeneration as evidenced by increased NFT scores.
Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown. This review summarizes recent findings regarding the role of tau oligomers in disease, including release from cells, propagation from affected to unaffected brain regions, uptake into cells, and toxicity via mitochondrial dysfunction. A greater understanding of tauopathies may lead to future advancements in regards to prevention and treatment.
The microtubule-associated protein tau can associate with various other proteins in addition to tubulin, including the SH3 domains of Src family tyrosine kinases. Tau is well known to aggregate to form hyperphosphorylated filamentous deposits in several neurodegenerative diseases (tauopathies) including Alzheimer disease. We now report that tau can bind to SH3 domains derived from the p85α subunit of phosphatidylinositol 3-kinase, phospholipase Cγ1, and the N-terminal (but not the C-terminal) SH3 of Grb2 as well as to the kinases Fyn, cSrc, and Fgr. However, the short inserts found in neuron-specific isoforms of Src prevented the binding of tau. The experimentally determined binding of tau peptides is well accounted for when modeled into the peptide binding cleft in the SH3 domain of Fyn. After phosphorylation in vitro or in transfected cells, tau showed reduced binding to SH3 domains; no binding was detected with hyperphosphorylated tau isolated from Alzheimer brain, but SH3 binding was ...
We have developed an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay for the measurement of Alzheimers disease (AD) abnormally hyperphosphorylated tau in cerebrospinal fluid (CSF). The assay, which recognizes attomolar amounts of tau, is approximately 400 and approximately 1300 times more sensitive than conventional enzyme-linked immunosorbent assay in determining the hyperphosphorylated tau and total tau, respectively. With this method, we measured both total tau and tau phosphorylated at Ser-396/Ser-404 in lumbar CSFs from AD and control patients. We found that the total tau was 215 +/- 77 pg/ml in cognitively normal control (n = 56), 234 +/- 92 pg/ml in non-AD neurological (n = 37), 304 +/- 126 pg/ml in vascular dementia (n = 46), and 486 +/- 168 pg/ml (n = 52) in AD patients, respectively. However, a remarkably elevated level in phosphorylated tau was only found in AD (187 +/- 84 pg/ml), as compared with normal controls (54 +/- 33 pg/ml), non-AD (63 +/- 34 pg/ml), and
Tau proteins promote the assembly and stability of microtubules in neuronal cells, and primarily in the distal portions of axons. Mutations in the MAPT gene are associated with a range of neurodegenerative diseases including Alzheimers disease, Picks disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. Hyperphosphorylation of tau proteins leads to the assembly of tangled filaments that are implicated in the pathogenesis of Alzheimers disease ...
TY - JOUR. T1 - Abnormal interaction of oligomeric amyloid-β with phosphorylated tau. T2 - Implications to synaptic dysfunction and neuronal damage. AU - Manczak, Maria. AU - Reddy, P (Hemachandra). PY - 2013. Y1 - 2013. N2 - Alzheimers disease (AD) is a progressive neurodegenerative mental illness characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. The purpose of our study was to determine the interaction between monomeric and oligomeric amyloid-β (Aβ) and phosphorylated tau in AD neurons. Using postmortem brains from AD patients at different stages of disease progression and control subjects, and also from AβPP, AβPPxPS1, and 3xTg-AD mice, we studied the physical interaction between Aβ and phosphorylated tau. Using immunohistological and double-immunofluorescence analyses, we also studied the localization of monomeric and oligomeric Aβ with phosphorylated tau. We found monomeric and oligomeric Aβ interacted with phosphorylated tau in ...
Tau is a family of neuronal proteins that bind to microtubules (the neurons transport system), and stabilize their formation and maintenance. In the human brain, Tau proteins constitute a family of 6 isoforms that is produced by alternative splicing of a single gene called MAPT (Microtubule-Associated Protein Tau). Research interest in tau proteins began to grow when tangled forms of these proteins were found to make up the paired helical filaments in brains of Alzheimers disease (AD) patients. Our webpage provides an introduction to Tau and the process by which it forms pathological neurofibrillary tangles, as well as providing information on our extensive selection of anti- Tau antibodies and recombinant proteins. BioLegend develops and manufactures world- class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.
The accumulation of microtubule-associated protein tau into fibrillar aggregates is the hallmark of Alzheimers disease and other neurodegenerative disorders, collectively referred to as tauopathies. Fibrils can propagate from one cell to the next and spread throughout the brain. However, a study shows that only small aggregates can be taken up by cultured neuronal cells. The mechanisms that lead to the breakage of fibrils into smaller fragments remain unknown. In yeast, the AAA+ chaperone HSP104 processes the reactivation of protein aggregates and is responsible for fragmentation of fibrils. This study focused on investigating the effects of molecular chaperones on tau fibrils and using HSP104 as a model system to test whether we can monitor fibril fracturing. The assays used to detect the chaperones actions on tau utilized acrylodan fluorescence, thioflavin T fluorescence, and sedimentation. Tau fibrils were either formed with a cofactor, heparin, to accelerate assembly or without a cofactor. In the
Purified anti-4R Tau Antibody - Tau proteins are microtubule-associated protein (MAPs) which are abundant in neurons of the central nervous system, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes and elsewhere.
Tau protein is a family of microtubule binding proteins, heterogeneous in molecular weight, that are induced during neurite outgrowth and are found prominently in neurofibrillary tangles in Alzheimers disease. The predicted amino acid sequences of two forms of tau protein from mouse brain were determined from complementary DNA clones. These forms are identical in their amino-terminal sequences but differ in their carboxyl-terminal domains. Both proteins contain repeated sequences that may be tubulin binding sites. The sequence suggests that tau is an elongated molecule with no extensive alpha-helical or beta-sheet domains. These complementary DNAs should enable the study of various functional domains of tau and the study of tau expression in normal and pathological states. ...
Immunotherapeutic approaches to treat tauopathies are being intensively pursued by both academia and industry. While active immunization strategies will likely not be a viable therapeutic approach due to concerns about auto-immunity and micro-hemorrhage, it could be useful for understanding the interface between the immune response and tau pathogenesis. Using active immunization against the 4R0N wild-type or P301L tau, we determined the most immunogenic epitopes in the central nervous system tau isoform. One of these epitopes (amino acids 21-27 GDRKDQG), a sequence that introduces a caspase cleavage DXXD motif and is linked to tau pathogenesis, is exclusively found in tau from primates, suggesting that the evolutionary insertion of this fragment could be an important reason for the emergence of tau pathogenesis in humans. In addition, we show that while non-transgenic and tau transgenic mice do produce some similar epitopes to wild-type and mutant human tau, they also produce anti-sera to unique ...
The question of how neurofibrillary tangles (NFTs) contribute to the profound loss of neurons in Alzheimers disease remains unsettled in part because of a dearth of suitable animal models. A handful of transgenic mouse strains exist that express various forms of tau, but they either die at a young age or differ markedly from the tau pathology seen in AD. Indeed, the reconstruction of tau pathology in cell and animal models remains an important goal, write researchers led by Eckhard Mandelkow in a paper, published last month, on the structural characteristics that allow human tau mutations to promote tau aggregation in vitro (von Bergen et al. 2001 See also comment by Peter Davies below).. A paper published on New Years Day provides a step in this direction. Led by Akihiko Takashima of the RIKEN Brain Science Institute in Saitama, Japan, first author Kentaro Tanemura and colleagues report their analysis of tau transgenic mice that enable the study of tau-induced neurodegeneration in vivo. The ...
Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β). We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2−/− mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2−/− mice for a period of eight months, followed by water maze testing at 12 months of age, immediately prior to sacrifice. We found that lithium significantly lowered hyperphosphorylated tau levels as measured by Western blot and immunocytochemistry. However, we found no apparent neuroprotection, no effect on spatial memory deficits and an increase in histological amyloid deposition. Aβ levels
The two pathological hallmarks of the devastating neurodegenerative disorder, Alzheimers disease, are amyloid plaques and tau protein tangles. Amyloid plaques and tau protein tangles are two brain abnormalities of Alzheimers disease. Amyloid plaques form due to the accumulation of the β-amyloid protein whereas the development of the toxic tau tangles is due to the aggregation of the tau protein.. Since scientists discovered that the gene variant ApoE4 was responsible for multiplying the risk of developing Alzheimers disease fourfold, researchers have been investigating the association between ApoE and both β-amyloid and the tau protein. Understanding these associations and how they link with disease progressions subsequently enables new targets to be identified for developing novel therapeutics to treat Alzheimers.. Surprising results regarding the tau protein were revealed recently in a US study discussed in Science. They took mice which were genetically engineered to produce a version of ...
Inflammatory. A bioluminescent marker for astrocytes tracks neuroinflammation in living tau-A152T mice. [Image courtesy of Sydow et al., Acta Neuropathologica Communications.]. "These are important and useful mouse models of tauopathy for both mechanistic studies and future anti-tau drug testing," commented Yadong Huang of the Gladstone Institute of Neurological Disease in San Francisco, who was not involved in either paper.. Most tau mutations that cause neurodegeneration are found in or near the proteins microtubule-binding repeats, and they typically cause the protein to aggregate. In contrast, tau-A152 sits away from the repeats in a proline-rich area that might be involved in intracellular signaling. Unlike the majority of tau mutations, which lead to frontotemporal dementia in people, A152T seems to boost risk for a variety of other conditions as well, including Alzheimers, and dementia with Lewy bodies.. One of the research groups led by Lennart Mucke at the Gladstone Institute used the ...
MT defects, a hallmark of tauopathies, contribute directly to neurodegeneration (Ballatore et al., 2007). Previous studies in both cell cultures and primary culture neurons reveal that overexpressed tau shows reduced MT binding to motor proteins and inhibits transport of cellular components, which lead to MT disruption and synaptic decay (Mandelkow et al., 2004; Thies and Mandelkow, 2007). However, how the overexpressed tau leads to MT defects in vivo remains poorly understood. Our previous work showed that increased MT acetylation in HDAC6 null mutants rescued tau-induced MT defects in both muscles and neurons (Xiong et al., 2013). In mammals, HDAC6 binds with tau directly, maintains site-specific tau phosphorylation and promotes tau accumulation (Cook et al., 2012; Ding et al., 2008). Thus, it is possible that HDAC6 mutations rescue tau-mediated MT defects by promoting degradation of phosphorylated tau. However, HDAC6 null mutation does not reduce the level of phosphorylated tau in Drosophila ...
Hrd1 Facilitates Tau Degradation and Promotes Neuron Survival. Shen, Y. X.; Sun, A. M.; Fang, S.; Feng, L. J.; Li, Q.; Hou, H. L.; Liu, C.; Wang, H. P.; Shen, J. L.; Luo, J.; Zhou, J. N. // Current Molecular Medicine;Feb2012, Vol. 12 Issue 2, p138 Intraneuronal accumulation of abnormal phosphorylated tau (p-tau) is a molecular pathology in many neurodegenerative tauopathies, including Alzheimers disease (AD) and frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17). However, the underlying mechanism remains unclear.... ...
3289 Introduction: The taxanes and other microtubule active drugs are important components of several chemotherapeutic regimens. Microtubule associated protein (MAP)-Tau promotes tubulin assembly and stabilizes microtubules in a physiological manner. Recently our laboratory found various levels of Tau expression in breast cancer cell lines and human breast cancer specimens. The goal of this research was to examine if modulation of Tau expression in breast cancer cell lines alters sensitivity to various chemotherapeutic drugs. Methods: Breast cancer cell lines (ZR75.1 and MCF7) with high level of Tau expression and high intrinsic resistance to taxanes were chosen. We used siRNA technology to knock down Tau expression. After 24 hours the transfected cells were incubated with Taxol, Taxotere, Vinorelbine and Doxorubicin for an additional 48-72 hours and then MTT assays were performed to assess cell survival. We also measured [H]3Taxol binding to microtubules in the presence and absence of Tau in an ...
Author Summary Neurodegenerative disorders, particularly the tauopathy Alzheimers disease, affect millions of people and cost billions of dollars a year in healthcare costs. Although effective treatments to delay or reverse cognitive decline are still unavailable, several approaches to address this medical need are being pursued. One such strategy involves ameliorating aberrant tau processing, as the characteristic tau tangles associated with the tauopathies are well-correlated with cognitive dysfunction, genetic mutations in tau lead directly to neurodegeneration, and experiments in animal models have yielded promising results. Two avenues are currently being explored: inhibition of kinase activity to reduce the presence of aberrant, hyperphosphorylated tau and means to prevent and reduce tau aggregation. We have taken a systems biology approach to understanding tau pathophysiology, creating a mathematical model to quantitatively explore the vulnerabilities in the tau network and identify effective
Tau protein plays an important role in the development of Alzheimers and other neurodegenerative diseases, collectively known as "taupathies." Tau normally functions to help maintain cell structure but in some brain diseases, it becomes abnormally modified, and can ultimately accumulate to form neurofibrillary tangles, a hallmark feature of Alzheimers disease and other taupathies. Most of the accumulation of tau protein into neurofibrillary tangles occurs inside nerve cells. However, recent evidence suggests that abnormal tau protein may be able to be transported from one nerve cell to nearby cells leading to the movement of abnormal tau through the brain. This finding has important implications for the progression of Alzheimers disease, but the mechanisms of this process are not yet understood. Tsuneya Ikezu, M.D., Ph.D., and colleagues have proposed a series of studies examining the mechanisms underlying the movement of abnormal tau protein throughout the brain. The researchers plan to test ...
Tau protein plays an important role in the development of Alzheimers and other neurodegenerative diseases, collectively known as "taupathies." Tau normally functions to help maintain cell structure but in some brain diseases, it becomes abnormally modified, and can ultimately accumulate to form neurofibrillary tangles, a hallmark feature of Alzheimers disease and other taupathies. Most of the accumulation of tau protein into neurofibrillary tangles occurs inside nerve cells. However, recent evidence suggests that abnormal tau protein may be able to be transported from one nerve cell to nearby cells leading to the movement of abnormal tau through the brain. This finding has important implications for the progression of Alzheimers disease, but the mechanisms of this process are not yet understood. Tsuneya Ikezu, M.D., Ph.D., and colleagues have proposed a series of studies examining the mechanisms underlying the movement of abnormal tau protein throughout the brain. The researchers plan to test ...
The microtubule-associated protein tau is present in the pathologic hallmarks of Alzheimers disease and its production and deposition have been implicated in the pathogenesis of the disease. We detected tau mRNA using in situ hybridization histochemistry in the hippocampus, visual cortex, and cerebellum, and compared its level in Alzheimers disease with controls. The amount of tau mRNA also was determined as a ratio of total polyadenylated mRNA in each area. A significant and gene-specific increase in tau mRNA hybridization was found in hippocampal fields CA4 and CA3, with a similar trend in the dentate gyrus. In contrast, no change was found in the visual cortex or cerebellum in Alzheimers disease. Increased hippocampal expression of tau mRNA also was present in cases of non-Alzheimers dementia. Enhanced tau mRNA may be a marker of attempted plasticity involving the cytoskeleton in neuronal populations affected by various neurodegenerative disorders.
Alzheimers disease (AD) is the leading cause of dementia, accounting for 50 to 80 percent of dementia cases, and the prevalence of the disease is projected to increase significantly with time. AD is characterized by severe cognitive decline with age, ultimately requiring continued caregiving and eventually death. The pathology of AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuron loss, and evidence of inflammation indicated by the presence of reactive microglia and astrocytes. Frontotemporal Lobe Dementia (FTLD) is a rare form of dementia that is related to AD, most notably in the pathology of hyperphosphorylated tau and macroscopic brain shrinkage. It has been defined as one of a host of tauopathies, and has a more rapid onset than AD. Symptoms that resemble personality changes, moreso than memory loss, are characteristic of these other tauopathies (FTLD is a representative of a whole
Targeting hyperphosphorylated tau by immunotherapy is usually emerging as a promising approach to treat tauopathies such as Alzheimers disease and frontotemporal dementia. female tangle mice (JNPL3 2 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 μg/ 125 μL; = 10 per group) for a total of 13 injections. Their behavior alpha-Amyloid Precursor Protein Modulator was assessed at 5-6 months of age and brain tissue was subsequently harvested for analyses of treatment efficacy. The treated mice performed better than controls around the traverse beam task (< 0.03) and had 58% less tau pathology in the dentate gyrus of the hippocampus (= 0.02). As assessed by western blots the antibody therapy reduced the levels of insoluble pathological tau by 14-27% (PHF1 < 0.05; PHF1/total tau < 0.0001) and 34-45% (CP13 or CP13/total tau < 0.05). Levels of soluble tau and sarkosyl soluble tau were unchanged compared with controls as well as total tau levels in all the ...
Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimers disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing
References for Abcams Recombinant Human Tau410 protein (ab72462). Please let us know if you have used this product in your publication
PubMed Central Canada (PMC Canada) provides free access to a stable and permanent online digital archive of full-text, peer-reviewed health and life sciences research publications. It builds on PubMed Central (PMC), the U.S. National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature and is a member of the broader PMC International (PMCI) network of e-repositories.
Alzheimers disease (AD) is characterised by neuropathological deposits of amyloid plaques and neurofibrillary tangles. In AD, tau is abnormally phosphorylated and forms aggregates which spread trans-synaptically throughout the brain. The non-receptor-associated tyrosine kinase fyn is up-regulated in a subset of tangle-bearing neurons in AD brain and fyn also phosphorylates tau. Most tau is axonally located, where it promotes microtubule stability. Both tau and fyn are found in dendrites, where they stabilise receptor complexes at the post-synaptic density. Tau is also trafficked to the plasma membrane in a phosphorylation-dependent process that requires fyn. Tau is also present in the extracellular space, which could play an important role in the spread of tau pathology in AD. The function of tau at the membrane, and the precise role of fyn in tau trafficking are unclear, but they suggest that fyn could contribute to tau propagation. Here, the role of fyn in tau release was investigated in ...
Introduction: A predominant molecular component analyzed in the study of neurodegenerative diseases is the presence of the Tau-GSK3β complex and its association with protein aggregation into the cell. Several evidences show that GSK3β has an important role in abnormal pattern of the phosphorylation of Tau. However, the molecular events that are governing this complex are unknown. Aim: To determine the effect of 17 β-estradiol treatment on the expression and association of Tau hyperphosphorylation responsible kinases. Methods: 17 β-estradiol treatments were realized in the hippocampus of ovariectomized adult wistar rats and in hippocampal primary cultures treated with β-amiloid. Protein complex association was assessed by co-immunoprecipitation, toxicity assay by LDH release and cell morphologic changes by confocal microscopy. Results: Our results show that 17β-estradiol produced dissociation of macromolecular complexes like Tau/GSK3β, Tau/GluR2/3, Tau/FAK, and Tau/Fyn in hippocampus of ...
Alzheimers disease (AD) is a widespread progressive neurodegenerative disorder characterized by the presence of neurofibrillary tangles consisting of hyperphosphorylated and truncated tau proteins and extracellular senile plaques composed of amyloid-β [46]-[51]. Previous studies have indicated that neuroinflammation significantly modulates the pathogenesis of AD by increased activation of brain immune cells and their potency to phagocytose and enzymatically degrade pathologic lesions [52]-[54].. In early stages of AD, microglia activation becomes protective and delays the disease progression by effective clearance of pathological lesions [55]-[57], while in the later stages, microglia lose their protective function and release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) [4],[5],[58]-[60]. It was shown that microglia cells isolated from the aged brains exhibit increased release of cytokines as compared to those from the young brains, ...
Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ1-42 and is induced by Aβ1-42 in vitro. Collectively, our data ...
We have also identified two additional conserved serine/threonine kinases as Tau modifiers. Activating expression of either the center divider kinase or a Drosophila homolog of the Tao1 kinase enhanced Tau toxicity. The center divider kinase is expressed in the developing Drosophila nervous system and has a well-conserved mammalian homolog (Matthews and Crews 1999). Tao1 is highly expressed in the rat brain (Hutchisonet al. 1998). These kinases represent attractive candidates for involvement in the pathogenesis of Alzheimers disease and related disorders. In future studies, it will be important to determine whether these kinases can directly phosphorylate Tau and whether the distribution or activity of the human homologs is altered in disease states. These enzymes will also be candidates for testing in vertebrate tauopathy models.. Tau isolated from the brains of patients dying with Alzheimers disease and related disorders characterized by abnormal Tau deposition is abnormally ...
Aberrant phosphorylation of tau protein is associated with a number of neurodegenerative disorders. The molecular mechanism by which tau phosphorylation is regulated under physiological and pathological conditions is not understood. Here we show that phosphorylation of a conserved T408 residue in the activation loop of the kinase domain of PAR-1, an established tau kinase, is critical for its activity. Mutations that render this site unphosphorylatable abolished the biological activity of PAR-1 and its biochemical activity in phosphorylating tau. Using a combination of biochemical and genetic analyses, we found that the tumor suppressor protein LKB1 is an upstream activating kinase that acts on the T408 site of PAR-1. Consistent with LKB1 acting upstream of PAR-1, we found that LKB1 promotes tau phosphorylation at PAR-1-dependent sites and that tauS2A, which is nonphosphorylatable by PAR-1, blocked the effect of LKB1 on tau toxicity.. Our results also demonstrate that PAR-1 activation and tau ...
The background of this work is the earlier observation that expression of pro-aggregant forms of Tau cause the typical signs of tau pathology (e.g. hyperphosphorylation, aggregation, loss of synapses and neurons, cognitive deficits), whereas anti-aggregant forms do not [56, 71, 72]. These results strongly supported the notion that the aggregation of Tau (or at least its propensity for β-structure) is intimately linked to the disease process, and appeared to suggest that anti-aggregant Tau is only a neutral bystander in the functioning of neurons. However, the mechanisms of Tau-induced toxicity are still uncertain, and therefore we wanted to characterize mice expressing anti-aggregant Tau in more detail in order to understand the principal differences between the two forms of Tau. To this end we analyzed regulatable mice expressing anti-aggregant repeat domain (TauRDΔKPP) and organotypic hippocampal slices (OHSCs) derived from them, and compared them with mice expressing the pro-aggregant ...
The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present i …
Tau is a major MAP of neurons. To date the most established function of tau is its promotion of assembly and maintenance of microtubules (Weingarten et al., 1975; Drubin and Kirschner, 1986). That tau might also play a role in the regulation of organelle transport was shown by Ebneth et al. (Ebneth et al., 1998) in CHO and differentiated Neuro 2A cells where upon transfection with tau, the anterograde kinesin-mediated mitochondrial/organelle movement was disrupted. The present study shows that the phosphorylation of tau by GSK-3β during differentiation might be involved in the regulation of the intracellular anterograde mitochondrial/organelle transport in small caliber neurites where tau represents a large proportion of total MAPs.. In the present study in PC12 cells differentiated by NGF or FGF2, the levels of tau and GSK-3β were upregulated simultaneously and the GSK-3β-mediated tau phosphorylation was increased at several sites canonic for proline-dependent kinases including the Tau-1 ...
Brain slices, tau protein analysis. Slices of mouse brains that have been stained (haematoxylin and eosin stain) and labelled for study and research into brain diseases. Labelling techniques using specific primary antibodies can be used to detect the distribution of specific proteins in tissues from control and experimental samples. Tau protein is an abundant neural protein, aggregations of which are thought to play a role in brain disorders such as Alzheimers disease. - Stock Image C023/8213
By Kiran Yanamandra, Tirth K. Patel, Hong Jiang, Suzanne Schindler, Jason D. Ulrich, Adam L. Boxer, Bruce L. Miller, Diana R. Kerwin, Gilbert Gallardo, Floy Stewart, Mary Beth Finn, Nigel J. Cairns, Philip B. Verghese, Ilana Fogelman, Tim West, Joel Braunstein, Grace Robinson, Jennifer Keyser, Joseph Roh, Stephanie S. Knapik, Yan Hu, David M. Holtzman. Science Translational Medicine ...
Research in our laboratory is focused on understanding the mechanisms maintaining or altering tau proteostasis in neurons, and their relevance in aging and Alzheimers disease (AD). Intracellular accumulation of neurofibrillary tangles of hyperphosphorylated misfolded tau proteins is one of the main hallmarks in many neurodegenerative diseases, including AD. Little is known about the mechanisms underlying tau dysfunction and neurofibrillary degeneration but a dysfunctional regulation of protein expression has been proposed to participate in the pathogenesis of AD and related tauopathies. In addition, it is unclear whether disturbances in the levels of microRNAs or other molecules that directly regulate tau proteostasis contribute to the pathogenesis of AD. Hence, investigating how certain microRNAs impact tau synthesis, hyperphosphorylation and accumulation in the disease is currently the main interest of our laboratory. In our research, we employ a variety of biochemical, cell culture, ...
From the WUSTL Newsroom…. Increased brain cell activity boosts brain fluid levels of a protein linked to Alzheimers disease, according to new research from scientists at Washington University School of Medicine in St. Louis.. Tau protein is the main component of neurofibrillary tangles, one of the hallmarks of Alzheimers disease. It has been linked to other neurodegenerative disorders, including frontotemporal dementia, supranuclear palsy and corticobasal degeneration.. "Healthy brain cells normally release tau into the cerebrospinal fluid and the interstitial fluid that surrounds them, but this is the first time weve linked that release in living animals to brain cell activity," said senior author David M. Holtzman, MD. "Understanding this link should help advance our efforts to treat Alzheimers and other neurodegenerative disorders associated with the tau protein.. The study appears online in The Journal of Experimental Medicine.. Tau protein stabilizes microtubules, which are long ...
Tau is a protein thought to play an important role in the molecular mechanisms of Alzheimers disease and related conditions. Normally, tau functions as part of the cell structure, but in Alzheimers disease it becomes abnormally modified by the addition of chemical phosphate groups through a process called phosphorylation. Excessive phosphorylation of tau leads to the disruption of important cellular structures and formation of neurofibrillary tangles, one of the characteristic features of Alzheimers disease in the brain. Kun Ping Lu, M.D., Ph.D., and colleagues have been studying the phosphorylation of tau and how it leads to tangle formation in nerve cells. The attachment of phosphate to tau can occur in two different orientations, known as cis and trans. Dr. Lus team found that cis-orientation of phosphate on tau is associated with tangle formation, but trans-orientation of phosphate on tau is not. Dr. Lu and colleagues have recently developed an antibody that binds to ...
Published on: March 29, 2015. by Elizabeth Gough-Gordon for MPR:. Memory problems associated with Alzheimers disease may one day be reversed with targeted immunotherapy, according to a new study appearing in theJournal of Neuroscience.. Scientists from the University of Texas Medical Branch at Galveston had previously found that anti-tau oligomer immunotherapy reduced levels of toxic tau oligomers and reversed memory deficits in an animal model of Alzheimers disease.. In the current research of passive immunotherapy with tau oligomer-specific monoclonal antibody, the removal of tau oligomers also reversed memory deficits and accelerated plaque deposition in the brains of mice. Unlike other tau immunotherapy treatments, this one only targeted the toxic oligomer form of tau, leaving the normal tau to carry out typical functions.. However, amyloid beta oligomer levels were also reduced with the immunotherapy, which indicates that the effects of amyloid beta may also be dependent on the presence ...
Stress hormones lead to Alzheimer-like protein modifications. Stress promotes neuropathological changes that are also seen in Alzheimers disease. Scientists from the Max Planck Institute of Psychiatry in Munich have discovered that the increased release of stress hormones in rats leads to generation of abnormally phosphorylated tau protein in the brain and ultimately, memory loss.. Protein deposits in nerve cells are a typical feature of Alzheimers disease: the excessive alteration of the tau protein through the addition of phosphate groups "" a process known as hyperphosphorylation "" causes the protein in the cells to aggregate into clumps. As a result, nerve cells die, particularly in the hippocampus, a part of the brain that plays an important role in learning and memory, as well as in the prefrontal cortex which regulates higher cognitive functions.. Fewer than ten percent of Alzheimer cases have a genetic basis. The factors that contribute to the rest of the cases are largely unknown. ...
Here we have used postmortem brain from all Braak stages to examine at which stage of disease development changes occur in key neurodegenerative disease proteins. We demonstrate that there is increased activity of calpain-1 from Braak stage III onwards in comparison to controls, extending previous findings that calpain-1 is upregulated at end-stage disease. In addition, activation of the tau kinases, GSK-3 and cdk5 were also found to occur in Braak stage II-III tissues, and these preceded global elevations in tau phosphorylation and the loss of post-synaptic markers observed in late-stage AD. In addition, we identified transient increases in total APP and pre-synaptic markers in Braak stage II-III, that were lost by end-stage AD, that may be indicative of endogenous compensatory responses to the initial stages of neurodegeneration. Our human brain data substantiate findings from many experimental models which have supported the hypothesis that sporadic AD arises in response to Aβ-mediated ...