Neurons were grown in tissue culture and stained with antibody toMAP2 protein in green and MAP tau in red using theimmunofluorescence technique. MAP2 is found only in dendrites and perikarya, while tau is found not only in the dendrites and perikarya but also in axons. As a result, axons appear red while the dendrites and perikarya appear yellow, due to superimposition of the red and green signals. DNA is shown in blue using theDAPI stain which highlights the nuclei. Image courtesyEnCor Biotechnology Inc.
In humans, theMAPT gene for encoding tau protein is located onchromosome 17q21, containing 16exons.[13] The major tau protein in the human brain isencoded by 11 exons. Exons 2, 3 and 10 arealternatively spliced, which leads to the formation of six tau isoforms.[14] In the human brain, tau proteins constitute a family of sixisoforms with a range of 352–441 amino acids. Tau isoforms are different in having either zero, one, or two inserts of 29 amino acids at theN-terminal part (exons 2 and 3) and three or four repeat-regions at theC-terminal part (exon 10). Thus, the longest isoform in theCNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).
TheMAPT gene has twohaplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copies of the gene, resulting in congenital defects.[15][16][17][18] The risk haplotype H1H1 in iPSC-derived cortical neurons revealed a higher expression of alpha-synuclein compared to H2H2, which may explain the association of haplotype with synucleinopathies such as Parkinson's disease.[19]
Six tau isoforms exist in human brain tissue, and they are distinguished by their number of bindingdomains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in thecarboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. Tau is aphosphoprotein with 79 potentialserine (Ser) andthreonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.[20]
Phosphorylation of tau is regulated by a host ofkinases, includingPKN, aserine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.[21] Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[22] The degree of phosphorylation in all six isoforms decreases with age due to the activation ofphosphatases.[23] Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example,PP2A andPP2B are both present in human brain tissue and have the ability todephosphorylate Ser396.[24] The binding of these phosphatases to tau affects tau's association with microtubules.
Phosphorylation of tau has also been suggested to be regulated byO-GlcNAc modification at various Ser and Thr residues.[25] Elevation of O-GlcNAc has been explored as a therapeutic strategy to protect against tau hyperphosphorylation.[26]
Tau proteins are found more often in neurons than in non-neuronal cells in humans. One of tau's main functions is to modulate the stability of axonalmicrotubules.[11][27] Other nervous systemmicrotubule-associated proteins (MAPs) may perform similar functions, as suggested by tauknockout mice that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.[28][29][30]
Although tau is present indendrites at low levels, where it is involved in postsynaptic scaffolding,[31] it is active primarily in thedistal portions ofaxons, where it provides microtubule stabilization but also flexibility as needed. Tau proteins interact withtubulin to stabilize microtubules and promote tubulin assembly into microtubules.[11] Tau has two ways of controlling microtubule stability:isoforms andphosphorylation.
The primary non-cellular functions of tau is to negatively regulatelong-term memory[27] and to facilitatehabituation (a form of non-associative learning),[27] two higher and more integrated physiological functions. Since regulation of tau is critical for memory, this could explain the linkage between tauopathies and cognitive impairment.
In mice, while the reported tau knockout strains present without overt phenotype when young,[28][37][38] when aged, they show some muscle weakness, hyperactivity, and impairedfear conditioning.[39] However, neither spatial learning in mice,[39][40][41] nor short-term memory (learning) inDrosophila[27] seems to be affected by the absence of tau.
The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration.[44] The actual mechanism of how tau propagates from one cell to another is not well identified. Also, other mechanisms, including tau release and toxicity, are unclear. As tau aggregates, it replaces tubulin, which in turn enhances fibrilization of tau.[45] Several propagation methods have been proposed that occur by synaptic contact such as synaptic cell adhesion proteins, neuronal activity and other synaptic and non-synaptic mechanisms.[46] The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.[47][48] Moreover, recent studies show that tau can coordinate up to three Zn²⁺ ions via distinct sites in the N-terminal, repeat, and C-terminal regions;[49] occupancy of two Zn²⁺ sites is sufficient to promote liquid–liquid phase separation (LLPS) of tau in vitro, linking zinc homeostasis to condensate-driven aggregation pathways.[50]
Tau is involved in uptake and release processes, which are known as seeding. Uptake of tau protein requires the presence ofheparan sulfate proteoglycans at the cell surface, which happens bymacropinocytosis.[51] On the other hand, tau release depends on neuronal activity. Many factors influence tau release such as, for example, the isoforms orMAPT mutations that change the extracellular level of tau.[52] According to Asai and his colleagues, the spreading of tau protein occurs from theentorhinal cortex to thehippocampal region in the early stages of the disease. They also suggested thatmicroglia were also involved in the transport process, and their actual role is still unknown.[53]
Tau protein has been found in the extracellular environment including Cerebrospinal fluid (CSF) and Interstitial fluid (ISF) under physiological and pathological conditions.[54] Low-density lipoprotein receptor-related protein 1 (LRP1) has been shown as the receptor for Tau internalization into cells.[55] However, studying Tau uptake in human neurons revealed that physiological Tau monomers mainly use LRP1 for internalization, while the uptake of pathological Tau aggregates depend on heparan sulfate proteoglycans.[56]
Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanism such asPAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activate other kinases (GSK-3 andCDK5) that cause disease-associatedphosphoepitopes.[57] The degree of toxicity is affected by different factors, such as the degree of microtubule binding.[58][59] Toxicity could also happen byneurofibrillary tangles (NFTs), which leads to cell death and cognitive decline.
Hyperphosphorylation of the tau protein (tauinclusions, pTau) can result in theself-assembly oftangles of paired helical filaments and straight filaments, which are involved in thepathogenesis ofAlzheimer's disease,frontotemporal dementia and othertauopathies.[60] All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the Alzheimer's disease brain. In otherneurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. Whenmisfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases. Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nervesynapses.[61]
Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.[62] Some aspects of how the disease functions also suggest that it has some similarities toprion proteins.[63]
Thetau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into paired-helical-filament (PHF) tau andneurofibrillary tangles (NFTs).[64] The stage of the disease determines NFTs' phosphorylation. In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 199, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231.[65] Through its isoforms and phosphorylation, tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state inpaired helical filaments (PHFs) in the AD brain.
Tau mutations have many consequences, including microtubule dysfunction and alteration of the expression level of tau isoforms.[66] Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation,protease action or exposure topolyanions, such asglycosaminoglycans. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1 (microtubule associated protein tau 1), MAPT 2 andubiquitin into tangles of PHFs. This insoluble structure damagescytoplasmic functions and interferes withaxonal transport, which can lead to cell death.[67][61]
Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients. It has been well demonstrated that regions of tau six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK), can form tau PHF aggregation in AD. Apart from the PHF6, some other residue sites like Ser285, Ser289, Ser293, Ser305 and Tyr310, located near the C-terminal of the PHF6 sequences, play key roles in the phosphorylation of tau.[68] Hyperphosphorylated tau differs in its sensitivity and itskinase as well asalkaline phosphatase activity[69] and is, along withbeta-amyloid, a component of the pathologic lesion seen in Alzheimer disease.[70][71] A recent hypothesis identifies the decrease of reelin signaling as the primary change in Alzheimer's disease that leads to the hyperphosphorylation of tau via a decrease in GSK3β inhibition.[72]
A68 is a name sometimes given (mostly in older publications) to thehyperphosphorylated form of tau protein found in the brains of individuals with Alzheimer's disease.[73]
In 2020, researchers from two groups published studies indicating that animmunoassay blood test for the p-tau-217 form of the protein could diagnose Alzheimer's up to decades before dementia symptoms were evident.[74][75][76]
Repetitive mildtraumatic brain injury (TBI) is a central component ofcontact sports, especiallyAmerican football,[77][78] and the concussive force of military blasts.[79] It can lead tochronic traumatic encephalopathy (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau.[80] After severe traumatic brain injury, high levels of tau protein in extracellular fluid in the brain are linked to poor outcomes.[81]
The term "prion-like" is often used to describe several aspects of tau pathology in varioustauopathies, likeAlzheimer's disease andfrontotemporal dementia.[82] Trueprions are defined by their ability to induce misfolding of native proteins to perpetuate the pathology. True prions, likePRNP, are also infectious with the capability to cross species. Since tau has yet to be proven to be infectious it is not considered to be a true prion but instead a "prion-like" protein. Much like true prions, pathological tau aggregates have been shown to have the capacity to induce misfolding of native tau protein.[83] Both misfolding competent and non-misfolding competent species of tau aggregates have been reported, indicating a highly specific mechanism.[84]
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