Microtubules contribute to diverse cellular processes such as cell morphogenesis, cell division, and intracellular trafficking [41, 42]. In cells, microtubules can change their lengths via dynamic instability . They can serve as tracks for organelle transport mediated by microtubule-dependent motor proteins such as the plus-end-directed motor kinesin and its relatives, or the minus-end-directed motor dynein [44, 45]. These motors can transport their cargoes, for example, mitochondria [46, 47], lysosomes , peroxisomes , and endocytotic or exocytotic vesicles  towards the cell periphery or back towards the microtubule organizing center (MTOC), respectively. It has been shown that tau protein affects axonal transport [17, 51, 52]. Tau protein alters intracellular traffic due to its tight binding to microtubules and probably detaches the cargoes from kinesin. Nevertheless, tau protein has no influence on speed of kinesin with cargoes . This implies that the phosphorylation of tau should play an important role because this modification regulates tau’s affinity to microtubules. Brain imaging of tau-protein tangles predicts the location of future brain atrophy in Alzheimer's patients a year or more in advance, according to a new study .Six isoforms of tau protein differ according to the contents of three (3R) or four (4R) tubulin binding domains (repeats, R) of 31 or 32 amino acids in the C-terminal part of tau protein and one (1N), two (2N), or no inserts of 29 amino acids each in the N-terminal portion of the molecule. These isoforms, which vary in size from 352 to 441 amino acid residues, are related to the presence or absence of sequences encoded by exons 2, 3, or 10. Inclusion of the imperfect repeat region encoding exon 10 leads to the expression of tau containing four microtubule-binding repeats (MTBRs) (4R tau: 0N4R, 1N4R, 2N4R), while exclusion of exon 10 results in splicing products expressing tau with three MTBRs (3R tau: 0N3R, 1N3R, 2N3R) [7, 14]. These six isoforms are also referred to as τ3L, τ3S, τ3, τ4L, τ4S, and τ4 . Primary sequence analysis demonstrates that tau consists of a half-N-terminal acidic portion followed by a proline-rich region and the C-terminal tail, which is the basic part of the protein. The polypeptide sequences encoded by exons 2 and 3 add acidity to tau, whereas exon 10 encodes a positively charged sequence that contributes to the basic character of tau protein. On the other hand, the N-terminal region has an isoelectric point (pI) of 3.8 followed by the proline-rich domain, which has a pI of 11.4. The C-terminal region is also positively charged with a pI of 10.8. In other words, tau protein is rather a dipole with two domains of opposite charge, which can be modulated by posttranslational modifications . Because each of these isoforms has specific physiological roles, they are differentially expressed during the development of the brain. For instance, only one tau isoform, characterized by 3R and no N-terminal inserts, is present during fetal stages, while the isoforms with one or two N-terminal inserts and 3- or 4R are expressed during adulthood .Despite in vitro formed tau polymers have been demonstrated by spectroscopy, laser scattering, and electron microscopy [120–123], recent findings demonstrate that prefibrillar tau oligomers can be formed in vitro by light-induced cross-linking of tau with benzophenone-4-maleimide (B4M) . These oligomers of tau were also observed in situ at the early stages of AD, when a monoclonal and specific antibody to these oligomeric entities of tau was assessed in the brain of AD cases . Oligomeric species of tau protein are reported to have increased toxicity over soluble and high-ordered fibrillary aggregates such as NFTs [124–126]. In transgenic mice that overexpress tau, most of the observed cognitive alterations emerged at stages of profound occurrence of multimeric aggregates of tau and prior to the formation of NFTs .
“Because they’re so prominent in microscopic examinations of the brain, they have become targets for potential therapies,” said Troncoso, who has spent decades studying the disease. “If you can remove or prevent the accumulation of beta-amyloid with a vaccine or an antibody, then you may prevent or slow down the development of the disease.”He and his colleagues discovered that the presence of tau disrupts the orderly structure of nuclear pores containing the major structural protein Nup98. In Alzheimer’s disease cells, there were fewer of these pores and those that were there tended to be stuck to each other.The recent study reveals that animal and human cells with Alzheimer’s disease have faulty nuclear pores, and that the fault is linked to tau accumulation in the brain cell.“That leads to the death of that neuron, and maybe the one next to it, and the one next to that one,” adds Petersen. “And if those neurons are in the memory part of the brain, then the person becomes forgetful.”The authors note, however, that it is not clear whether the Nup98-tau interaction uncovered in the study just occurs because of disease or whether it is a normal mechanism that behaves in an extreme fashion under disease conditions.
tau protein, which forms part of a microtubule. The microtubule helps transpot nutrients and other important substances from one part of the nerve cells to another. Axon are long threadlike extensions that conduct nerve impulses away from the nerve cells; dendrites are short branched threadlike extensions that conduct nerve impulses toward the verve cell body. In Alzheimer´s disease the tau protein is abnormal and the microtubule structures collapse.Professor Donna Wilcock describes neurofibrillary tangles, which form inside the neuron in Alzheimer's disease and are composed of tau proteins. In the hippocampus of AD patients, the maturation of NFTs is reported to be unsynchronized. Therefore these structures have different stages of tau processing . It was reported that different populations of NFTs in the same hippocampal area were mutually exclusive when they were composed of either Asp421- or Glu391-truncated tau with no colocalization at any single point during the maturation of the NFTs . During the progression of the disease, Asp421-truncation is an early event that precedes the second truncation of the C-terminus at the Glu391, the later occurring from intermediate to advanced stages of NFTs evolution . A recent report indicates that tau protein in NFTs may be dually subjected to both apoptotic and proteosomal proteolysis since strong ubiquitination was found in Asp421-truncated tau associated with the neurofibrillary pathology in AD .
Alzheimer's Disease is the most common neurodegenerative disorder. A hallmark of this disease is aggregation of the protein Tau into fibrillar tangles, which is ultimately linked to neuronal death 1,2.. “Tau is a normal protein that exists in every cell in the body,” said Juan Troncoso, director of the Brain Resource Center at the Johns Hopkins University School of Medicine. Our cells’ overall structures are supported by microtubules, hollow tubes that give cells their shape. Along with another protein called tubulin, tau binds to these microtubules to keep them strong and stabilized.Braak stages of AD neuropathology base on the pattern of neurofibrillary change (NFT, Neuropil threads and plaques dystrofic neurites) , Although clinic-pathological correlations were not made, Braak and Braak did speculate that the entorhinal stage (I-II) represents clinically silent periods of the disease with NFT involvement confined to trans-entorhinal layer pre-alpha. Limbic stages (III/IV) correspond with clinically incipient AD, and NFT involvement of CA1, and neocortical stages (V/VI) represent fully developed AD, with NFT involvement of all areas of association cortex. Tau protein is mainly intracellular. However, several studies have demonstrated that full-length Tau can be Alzheimer's disease is characterized by redistribution of the tau protein pool from soluble to.. But with brain imaging and early detection, researchers are now able to study these proteins long-term, watching them accumulate as the disease progresses. Many think that if we can watch them build up, we can find a way to break them back down — ultimately curing Alzheimer’s. That’s easier said than done, of course, because both tau and beta-amyloid proteins wreak havoc in their own, separate ways.
.But for reasons unknown, tau proteins in Alzheimer’s patients go through a process called hyperphosphorylation. Here, the addition of phosphate molecules causes tau proteins to break down and lose their shape. Too weak to support microtubules, they begin detaching and sticking to each other instead. The degenerate tau proteins tangle together inside of neurons, growing large enough to block the chemical and electrical signals that travel toward the synapses and on to neighboring cells. Clusters of dead nerve cells. Hard plaques cemented between cells and thick tangles of proteins twisted up inside the cells themselves.
2Third Faculty of Medicine, Charles University in Prague, Ruská 87, 100 00 Prague 10, Czech Republic Alzheimer's disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-beta (Abeta) plaques, and clinically by progressive dementia By combining of antibodies that map different regions of the molecule of tau, a continuous and specific pathway of conformational changes and truncation of tau protein has been proposed to occur during the maturation of NFTs. These antibodies are, namely, conformational and phosphorylation-dependent and recognizing truncation sites [66, 67, 145].
Scheme illustrating the early steps of aggregation and polymerization of tau protein in Alzheimer´s disease. (A) The model starts with the appearance of PHF-core tau in cytoplasm of susceptible neurons. (B) The high binding capacity of PHF-tau results in the assembly of dimers of PHF-core and intact tau molecules in the cytoplasm. (C) The phosphorylation of intact tau would be an early event to hide the toxic soluble aggregates of molecules. (D). The high affinity and stability of the proto-filaments that make up the mature intracellular NFT allows tau molecules to form PHFs. (E) With the death of the neuron, the PHF-core subunit becomes exposed again in the extracellular space following proteolysis. Further details are described in the text.The phosphorylation of tau regulates its activity to bind to microtubules and stimulate their assembly as previously outlined. A normal level of phosphorylation is required for the optimal function of tau, whereas the hyperphosphorylated state makes tau to lose its biological activity. Regarding the potential propensity of tau protein to be phosphorylated, it was reported that the longest variant of tau protein (441 amino acid) holds about 80 potential serine or threonine phosphorylation sites . Most of these potential sites are located at the vicinity of the MTBR in the proline-rich region and in the C-terminal extreme of the molecule of tau protein [16, 74] with the exception of Ser262, Ser293, Ser324, and Ser356 (motif KXGS) in R1, R2, R3, and R4 domains [75, 76]. In the disease the abnormal phosphorylation of tau could be, but not mutually exclusive, the result of upregulation of tau kinase(s) or downregulation of tau phosphatase(s) [62, 74]. A number of these enzymes have been evaluated and those kinases that are believed to play the most important role in phosphorylation of tau in the brain include GSK-3β, cyclin-dependent kinase 5 (cdk5), cAMP-dependent protein kinase (PKA), and calcium/calmodulin-dependent kinase II (CaMK-II) . GSK-3β may play major role in regulating tau phosphorylation in both physiological and pathological conditions. GSK-3β can phosphorylate tau on Ser199, Thr231, Ser396, Ser400, Ser404, and Ser413in vivo and in vitro (numbered according to the longest tau isoform), residues that are mostly phosphorylated in PHF-tau . Aforementioned phosphorylation at Thr231 causes a local conformational change that allows the access of GSK-3β or other kinases to further phosphorylate tau. On the other hand, a complementary and opposite effect is for PP1, PP2A, PP2B, and PP2C that can dephosphorylate tau protein in vitro . The activity of PP2A has been found to be reduced in selected areas of the brain of AD patients . Overall tau phosphoprotein is at least three- to fourfold more hyperphosphorylated in the brain of AD patients than that in the brain of aged nondemented individuals .Alzheimer’s disease does not go away and gets worse over time. It is the sixth most common cause of death in adults in the United States, where an estimated 5.7 million people have the disease.Studies on the causes of amyotrophic lateral sclerosis, frontotemporal, and other types of dementia have suggested that flaws in these nuclear pores are involved somehow.As of now, treatments for Alzheimer’s are limited. There are a handful of drugs and lifestyle adjustments that can ease symptoms, and studies on fasting diets are starting to show early promise. But researchers are confident that tau and beta-amyloid proteins hold the key to untangling Alzheimer’s.
, Third Faculty of Medicine, Faculty Hospital Královské Vinohrady, Charles University in Prague, Šrobárova 50, 100 34 Prague 10, Czech RepublicThe pathological effect of C-terminus truncated tau over the normal functioning of the cells has been assessed in cultured cells and transgenic animal models. By using neuronal and nonneuronal cells, overexpression of truncated tau protein produces several alterations in the organization and functioning of membranous organelles, such as mitochondria and the endoplasmic reticulum. Even some examples of cell death by apoptotic mechanisms also have been reported [148–156]. In transgenics animals, truncated-tau carrying rodents have developed alterations in cognitive performance associated with neuronal death and abnormal aggregation of cleaved tau [100, 157–162].Professor Kenneth Kosik discusses the biochemistry of Alzheimer's disease in relation to acetylcholine and cholinergic deficiency.By using a phosphorylation-dependent monoclonal antibodies against tau and mass spectrometry, it was reported that at least 39 phosphorylated sites in the tau molecule are associated with native PHF isolated from the brain of AD patients . One protein, called tau, is very closely linked to the disease, with tangles of tau thought to be one Another protein - beta amyloid - is also linked to Alzheimer's and can be detected in similar tests
Professor Kenneth Kosik discusses the tau protein and its relationship to the neurofibrillary tangles found in Alzheimer's disease. Eckhard Mandelkow (DZNE, Bonn-Germany) expuso en el IV Congreso Internacional sobre Investigación e Innovación en Enfermedades Neurodegenerativas (CIIIEN).. They also observed another curious change involving Nup98 inside Alzheimer’s disease brain cells. In cells with aggregated tau, the Nup98 was “mislocalized” instead of staying in the nuclear pore.
Unfortunately, becoming forgetful is only the beginning. As plaques and tangles spread from the hippocampus to the cerebral cortex, behavior, reasoning and language start to fade, too. This degradation continues until patients can no longer perform basic bodily functions, like eating and swallowing. The result is ultimately death.Tau protein is present in a greater extent in axons from neurons, but it also occurs in the oligodendrocytes. Another microtubule-binding protein referred to as MAP2 is located in the somatodendritic compartment of neurons, whereas MAP4 is much ubiquitous .The discovery sheds new light on the origins of this most common cause of dementia, a hallmark of which is the buildup of tangled tau protein filaments in the brain.
Eventually, the detached tau molecules form long filaments, or neurofibrillary tangles, that disrupt the brain cell’s ability to communicate with other cells. Alzheimer's disease is characterized by both deposit of an extracellular protein, beta-amyloid (or Abeta), which leads to the formation of beta-amyloid plaques, and by abnormal function of the Tau.. Alzheimer disease (AD) is a chronic neurodegenerative disease and the leading cause of dementia. Tangles are composed of hyperphosphorylated tau protein(a microtubule-associated protein)
This is a characteristic of tau protein in Alzheimer's disease and several tauopathies associated Alzheimer's disease is characterized by two main pathological hallmarks in the human brain: the.. Altered tau forms characteristic pathogenic inclusions in Alzheimer's disease and related Tau protein is a microtubule-associated protein (MAP) expressed abundantly in neurons and, to a lesser.. 3Department of Cell Biology, Center of Research and Advanced Studies, National Polytechnic Institute, Avenue Instituto Politecnico Nacional 2508, 07360 Mexico City, DF, Mexico
While amyloid precursor proteins (APP) — beta-amyloid’s parent protein — are best known for their contribution to Alzheimer’s disease, they might not deserve such a bad rap. APP is abundant in the brain and is found in synapses, tiny bridges that allow neurons to pass chemical and electrical signals to one another. While the main function of APP is unknown, some scientists think they help guide neurons through the brain during early development, or help cells attach to one another. But whatever use our bodies have for APP, it can turn into a deadly problem under the right conditions.The human tau gene is located over 100 kb on the long arm of chromosome 17 at band position 17q21 and contains 16 exons. Exon 1 is part of the promoter and is transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive exons. Exons 2, 3, and 10 are alternatively spliced and manifesting in the adult brain. Exon 2 can appear alone, but exon 3 never appears independently of exon 2 . In the central nervous system, alternative splicing of exons 2, 3, and 10 results in the appearance of six tau isoforms that are differentially expressed during development of the brain .Tau protein binds microtubules through some repeated domains (R1–R4) (encoded by exons 9–12) located at the C-terminus of the molecule (Figure 2) . Each repeat consists of stretches of a highly conserved 18 residues that are imperfectly repeated three times in the fetal tau protein and four times in the adult specific form . The repeats are separated from each other by 13- or 14-residue spacer regions. The main function of tau, aforementioned as a promoter of tubulin polymerization, depends mostly on the MTBR [35, 36]. It has been reported that in vitro tau protein increases the rate of microtubule polymerization and concomitantly inhibits its rate of depolymerization . The 18-amino-acid repeats bind to microtubules through a flexible array of distributed weak sites. The adult form of tau promotes assembly of microtubules more actively than fetal forms [14, 38]. Interestingly, the most potent part that induces microtubule polymerization is the interregion between repeats 1 and 2 (R1-R2 interregion) and more specifically the peptide 275KVQIINKK280 within this sequence [7, 39]. This R1-R2 interregion is unique to 4R tau, adult specific, and responsible for the difference in the binding affinities between 3R and 4R tau [7, 35]. Recent evidence supports a role for the MTBR in the modulation of the phosphorylation state of tau protein. A direct and competitive binding has been demonstrated between this region (residues 224–236 according to the numbering of the longest isoform) and the microtubule on one hand and the same region with the PP2A on the other hand . As a consequence, microtubules could inhibit PP2A activity by competing for binding to tau at the MTBR.Scientists from Massachusetts General Hospital (MGH) in Charlestown and the Johns Hopkins School of Medicine in Baltimore, MD, led the study, which set out to investigate how tau protein might contribute to brain cell damage.This paper was supported by the Project of Excellence in Basic Research (No. P 304/12/G069) from the Grant Agency of Czech Republic. G.-S. Francisco was supported by CONACyT-Mexico Grant CB-152535.
Exactly what causes Alzheimer’s and other forms of dementia is still a mystery to science. Evidence suggests that a combination of environment, genes, and lifestyle is involved, with different factors having different amounts of influence in different people.When this happens, for reasons Petersen and other researchers aren’t exactly sure of, APP is chopped into strands of amino acids that the brain can’t metabolize, called beta-amyloid proteins. Unable to break down, these proteins start sticking together, ultimately forming hard plaque deposits in the synapses between cells. Beginning in the hippocampus, these dense clusters block communication between neurons and kick-start cell death, triggering a loss of memory. And things only get worse from there.Neuropathological hallmarks of Alzheimer´s disease. Double labelling with tau antibody (green channel) counterstained with thiazine red (red channel). A) A classical neuritic plaquein which an amyloid fibrillar plaque (Aβ), recognized by thiazine red, is associated with dystrophic neurites (arrows). B). Pre-tangle cells are characterized by diffuse granular deposits throughout the perinuclear area (small arrow) and proximal processes. C) A neurofibrillary tangle that is strongly labeled by tau antibody and colocalized with tiazine red. (A,B) projection of 20 and 9 confocal microscopy sections, respectively, each of 1.0 μm thickness. Professor Kenneth Kosik discusses the tau protein and its relationship to the neurofibrillary tangles found in Alzheimer's disease. Tau is the protein that is formed in the neurofibrillary tangle.. Brain cells, or neurons, have internal structures known as microtubules that support the cell and its function. They are highly active cell components that help carry substances from the body of the cell out to the parts that connect it to other cells.
These studies proposed that not only the number of NFTs but also the state of proteolysis of the C-terminus which is associated with conformational changes (structural modification along the tau molecule) defines the progression of AD . All these findings together may support the relevance of truncation of tau protein as a pathogenic event and reliable marker for both diagnosis and therapeutic targeting in AD.Professor Kenneth Kosik describes senile plaques, an extracellular collection of a-beta protein. It is one of the hallmarks of Alzheimer's disease. But for reasons unknown, tau proteins in Alzheimer's patients go through a process called But researchers are confident that tau and beta-amyloid proteins hold the key to untangling Alzheimer's “APP is produced in the brain and is normally metabolized by an enzyme called alpha secretase, which cuts it in half and flushes it out with no problems,” says Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center. “But in people who develop Alzheimer’s disease, instead of being cut by alpha secretase, APP is cut by two other enzymes — beta secretase and gamma secretase.”
Tau proteins can convert from an inert shape to a misfolded shape that seeds the growth of fibers that contribute to the One such protein is Tau, which aggregates in people with Alzheimer's disease At cellular level, abnormal phosphorylation of tau introduces alterations in several processes which are directly regulated by the suitable organization of the microtubule network. In a normal mature neuron, tubulin is present in over tenfold excess of tau, and thus practically all tau protein is microtubule bounded in the cell [81, 82]. In neurons affected in AD, abnormally phosphorylated cytosolic tau (AD P-tau) neither binds to tubulin nor promotes microtubule assembly [83–85]. Instead, this protein inhibits the assembly and disrupts the microtubule organization . Moreover, it was reported that abnormally phosphorylated tau protein disengages normal tau from microtubules into the cytosolic phase , as much as 40% of the abnormally hyperphosphorylated tau in the brain of AD patients is present in the cytosol and not polymerized into paired helical filaments (PHFs) or forming NFTs . The AD P-tau also removes the other two major neuronal MAPs, MAP1 and MAP2, from microtubule lattice . This toxic feature of the AD P-tau appears to be solely due to its abnormal phosphorylation state because dephosphorylation of AD P-tau rescues this protein to perform its normal tasks . Tau protein containing many phosphorus groups (P-tau) can produce neurofibrillary tangles, which Alzheimer disease is currently diagnosed based on cognitive changes and by ruling out other causes..
Brain studies of people with the disease — together with postmortem analyses of brain tissue — have revealed much about how Alzheimer’s changes and harms the brain. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend.. “Under disease conditions,” explains co-senior study author Bradley T. Hyman, the director of the Alzheimer’s Unit at MGH, “it appears that tau interacts with the nuclear pore and changes its properties.”
Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.Professor Kenneth Kosik discusses neurofibrillary tangles, which form inside a cell and are made up of a protein called tau. There is a strong relationship with plaques and amyloid deposition.Alzheimer’s disease (AD) is the most common type of dementia characterized by memory impairment and alteration of diverse cognitive abilities. In association with the global trend of prolonging human life and increasing number of elderly in the human population, AD becomes one of the most important health and socioeconomic problems of the present. AD and related tauopathies are histopathologically characterized by slow and progressive neurodegeneration, which is associated mostly with intracellular accumulation of tau protein leading to the so-called neurofibrillary tangles (NFTs) and other inclusions containing modified tau . Tau protein was discovered in the mid-1970s of the 20th century by studying factors necessary for microtubule formation. Tau protein promotes tubulin assembly into microtubules, one of the major components of the neuronal cytoskeleton that defines the normal morphology and provides structural support to the neurons . Tubulin binding of tau is regulated by its phosphorylation state, which is regulated normally by coordinated action of kinases and phosphatases on tau molecule [3, 4]. In pathological conditions, such as the case in AD, not only does abnormal phosphorylation of tau protein decrease its tubulin binding capacity leading to microtubule disorganization, but also this protein self-polymerizes and aggregates in the form of NFTs [5, 6].
Professor Kenneth Kosik defines Alzheimer's disease as a slowly progressing illness that deteriorates the brain and impairs many major cognitive functions.For instance, overexpression or mislocalization that increase intracellular concentration of tau may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin so that the minus-end-directed transport by dynein becomes more dominant . Inhibition of transport to the plus-end of microtubule slows down exocytosis and affects the distribution of mitochondria which become clustered near to the MTOC. The absence of mitochondria and endoplasmic reticulum in the peripheral regions of the axons could produce a decrease in glucose and lipid metabolism and ATP synthesis and loss of Ca2+ homeostasis  that leads to a distal degeneration process referred to as “dying back” of axons . Moreover, phosphorylated tau protein has affinity to the kinesin and therefore is transported to the distal sites of neuropil. This may account for the observation that tangle pathology in AD appears to initiate distally and then spreads in a retrograde fashion to the perikaryon. This process may be a mechanism to protect the stability of the microtubules by transporting hyperphosphorylated tau more rapidly to other cellular locations where tau can form aggregates .
Schematic representation of the functional domains of the largest tau isoform (441 amino acids). The projection domain, including an acidic and a proline-rich region, interacts with cytoskeletal elements to determine the spacing between microtubules in axons. The N-terminal part is also involved in signal transduction pathways by interacting with proteins such as PLC-γ and Src-kinases. The C-terminal part, referred to as the microtubule-binding domain, regulates the rate of microtubules polymerization and is involved in binding with functional proteins such as protein phosphatase 2A (PP2A) or presenilin 1(PS1). Tau protein is a microtubule-associated protein, predominantly expressed in the neurons, closely In Alzheimer's disease, neurofibrillary tangles composed of hyperphosphorylated tau and ubiquitin..
With brain imaging and other techniques, researchers have been digging into the roots of the proteins associated with Alzheimer’s disease for decades. We now have a good idea of how they form, but it’s the why that’s missing.Copyright © 2012 Michala Kolarova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Researches have described a new technique to find out how Alzheimer's disease (AD) affects nerve cells The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau) Caspases are cysteine proteases that cleave aspartic acid residue in the canonical consensus sequence DXXD on the carboxy side of molecule. These enzymes participate in a proteolytic cascade leading to cell death via apoptosis. The major killer caspase in neurons is caspase 3 . Members of the caspase family play a critical role in Aβ-induced neuronal apoptosis  and are activated in apoptotic neurons in AD . It was known that tau protein contains several canonical sites for caspase cleavage [142, 143], from which a susceptible residue at Asp421 was reported to be cleaved in vitro by caspase 3 . The cleavage at Asp421 released a discrete peptide (Ser422-Leu441) that is capable of forming an amphipathic α-helix . Tau protein truncated at Asp421 assembled more readily than the full-length molecule [72, 144]. When a synthetic peptide comprising the fragment after caspase cleavage was added back to the tau molecule in a polymerization paradigm, assembly of this protein was inhibited.Recent studies demonstrated that hyperphosphorylation of tau occurs before its cleavage [97, 98] and that tau cleavage takes place before NFT formation . In an in vitro model of ethanol-induced neuronal apoptosis, hyperphosphorylation of tau occurs before tau cleavage [98, 100]. Altogether, these results may indicate that abnormal phosphorylation is a key event that triggers the pathological aggregation of tau in AD. Tau proteins are microtubule-associated proteins that are abundant in neurons in the central CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease
Similarly, tau protein is hyperphosphorylated by GSK3 and other kinases to first form paired helical filaments and A brief introduction to the tau protein and how it contributes to Alzheimer's disease Proteolytic cleavage of tau protein, as an alternative mechanism involving in the abnormal aggregation of tau, was early proposed by Whischik’s group at Cambridge University after extensive biochemical analysis of the minimal structure of the PHFs [69, 127, 128]. The minimal component of PHFs, referred to as the PHF core, was mostly composed of a fragment of tau only containing the region of the MTBR and ending at the position Glu391. Until today, identification of the enzyme that produces this proteolytic cleavage is uncertain. However, the presence of this truncation associated with the neurofibrillary pathology has been demonstrated in the brain of AD patients [129, 130]. Furthermore, from in vitro paradigms of polymerization, tau constructs lacking the carboxy tail assembled much faster and to a greater extent than full length tau . Despite these early evidences, attention was not focused for a while on the proteolysis of tau, and its contribution to the disease was uncertain. New findings show aberrant proteolysis in the brain of AD cases associated with programmed cell death [132, 133]. Further studies were dedicated to investigate the contribution of apoptosis and associated caspases into the neurodegenerative process underlying AD. In this regard, apoptotic cells were observed to proliferate in areas of the brain that were affected by fibrillary accumulation of tau protein and amyloid-β deposits [134–136]. Concomitantly, increased expression of several enzymes of the family of caspases was reported in the brain of AD cases [99, 137, 138].
Amyloid-β peptide (Aβ) and tau protein deposits in the human brain are the pathological hallmarks of Alzheimer's disease (AD). Tau is a class of proteins that are abundant in nerve cells and perform the.. However, in people with Alzheimer's disease, tau proteins — for unknown reasons — collapse into Once the tau protein gets out of control and becomes toxic tau protein, there seems to be a chain..