In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration
This fragment was proposed to be generated by caspases (although not caspase 3).
However, tau aggregates are also observed in the brains of some aged individuals with a condition known as primary age-related tauopathy (PART)
Tau aggregation decreases levels of soluble functional tau, which may result in microtubule disassembly as well
In the longer term, however, these tau aggregates may sequester other cell components, finally compromising neuronal functions
The interaction of tau with FYN may regulate the postsynaptic targeting of FYN, and thereby mediate Aβ‑induced excitotoxicity
Genetic deficiency of tau protects against excitotoxicity caused by Aβ or other excitotoxins in mice that overexpress human amyloid precursor protein (APP), in mice that express human APP and human presenilin 1 (PS1), and in mice that express mutant Scn1a (the gene encoding the voltage-gated sodium channel subunit Nav1.1), as well as in mice lacking the voltage-gated potassium channel Kv1.1 subunit
Tau aggregation could be accelerated by cofactors such as polyanions that compensate for the repulsive positive charges of tau
Conversely, tau aggregation can be induced in vitro efficiently by polyanionic cofactors, regardless of phosphorylation
In cultured neurons, missorted dendritic tau may mediate toxicity that is induced by Aβ or other stressors by promoting the translocation of tubulin tyrosine ligase-like enzyme 6 (TTLL6) into dendrites, and the severing of microtubules by spastin
To date, the physiological function of dendritic tau has not been well characterized. It may be involved in the regulation of synaptic plasticity, as pharmacological synaptic activation induces translocation of endogenous tau from the dendritic shaft to excitatory postsynaptic compartments in cultured mouse neurons and in acute hippocampal slices
Hyperphosphorylation, mutations and overexpression of tau can drive the mislocalization of tau into postsynaptic spines, resulting in synaptic dysfunction
Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD
This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation
In an analogy to the evolution of concepts in the ‘amyloid cascade hypothesis’, which proposes that soluble oligomers — rather than insoluble aggregates of amyloid peptides — are the causative agents of neurodegeneration in AD, recent studies have suggested tau oligomers to be the toxic species, and indeed levels of SDS-stable tau oligomers are increased in AD and PSP brains.
Some studies showed in cell toxicity assays that tau oligomers made from pro-aggregant recombinant tau were toxic to cultured cells; other studies in cultured neurons found that oligomers induced only local neurotoxicity that led to loss of spines
The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD.
It can do this by influencing the function of the motor proteins dynein and kinesin, which transport cargoes towards the minus ends (towards the cell body) and plus ends of microtubules (towards the axonal terminus), respectively (FIG. 3).
Finally, inhibition of mitochondrial complex I (for example, using annonacin or MPP+ (1‑methyl‑4‑phenylpyridinium)) upregulates expression of the splicing factor SRSF2, thus promoting expression of 4R tau in human neurons.
In brains of individuals with AD, neuron loss in the superior temporal sulcus region exceeds the number of NFTs more than sevenfold, implying that the majority of neurons probably die without having developed NFTs
Tau phosphorylated at Ser262 or Ser356 cannot be recognized by the C terminus of HSP70‑interacting protein–heat shock protein 90 (CHIP–HSP90) complex and is thus spared from proteasomal degradation
Tau is known to be ubiquitylated through Lys48 linkages by CHIP for proteasomal degradation
Notably, one study demonstrated that tau can also be ubiquitylated through Lys63 linkages by TNF receptor-associated factor 6 (TRAF6) — again, for proteasomal degradation
It is not clear whether the discrepancy between these results is due to the differences between the knockout mouse lines; nevertheless, both papers point to some involvement of tau in neurogenesis
For example, hyperphosphorylated tau but not unphosphorylated tau can interact with the kinesin-associated protein JUN N‑terminal kinase-interacting protein 1 (JIP1) and thus impair the formation of the kinesin complex,which mediates axonal transport
Third, some evidence suggests that expression of tau mRNA-binding proteins (such as RAS GTPase-activating protein-binding protein 1 and minor histocompatibility antigen H13) promotes the formation of ribonucleoprotein granules, resulting in a shift towards the expression of larger tau isoforms (such as high-molecular-weight tau and E3‑containing tau isoforms).
Owing to the additional repeat domain R2, 4R tau shows higher affinity for microtubules than does 3R tau, and is therefore more efficient at promoting microtubule assembly
Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD)
Fifth, tau may bind to the p150 subunit of dynactin and thereby facilitate the association of dynactin with microtubules, which stabilizes the interaction of dynein with microtubules and thus supports transport by dynein
Tau thereby stabilizes microtubules, promotes microtubule assembly and, in particular, regulates the dynamic instability of microtubules that allows reorganization of the cytoskeleton.
Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules
Notably, tau has intrinsic acetyltransferase activity and so can catalyse auto-acetylation at certain Lys sites, including Lys280
First, hyperphosphorylation of tau might induce tau missorting from axons to the somatodendritic compartment, which can cause synaptic dysfunction
In human AD brains, the missorting of tau into dendrites represents one of the early signs of neurodegeneration
In addition, as tau is involved in multiple novel functions, including iron transport, neurogenesis, LTD and neuronal DNA protection (as discussed above), the loss of function of tau may also lead to neurodegeneration via impairment of these processes.
In adult neurons, tau mainly distributes into axons, where it interacts with microtubules through the repeat-domain and flanking regions.
First, tau competes with kinesin or dynein motors for binding to microtubules, reducing the binding frequency, motile fraction and run length of kinesin and dynein (without changing the motor velocity of kinesin and dynein), and thereby slowing down both anterograde and retrograde transport
Fourth, tau can regulate the release of cargo vesicles from kinesin chains by activating PP1 and glycogen synthase kinase 3β (GSK3β) via the 18 residues at the N terminus of tau
In addition, tau seems to be essential for axonal elongation and maturation, as knockdown of tau in cultured rat neurons inhibits neurite formation, whereas overexpression of tau promotes the formation of neurites even in non-neuronal cells1
These studies indicate that the endogenous tau plays a part in regulating neuronal activity
Intraneuronal iron accumulation, neuronal loss in the substantia nigra and a severe decline in locomotor functions were observed in 12‑month-old tau-knockoutmice
Although tau function can be partly compensated by other, redundant microtubule-associated proteins (for example, MAP1A), the behavioural impairments observed in aged (~12‑month-old) tau-knockout mice indicate that tau is necessary for normal neuronal and brain function.
This study revealed that tau deficiency can cause iron accumulation inside neurons by preventing the trafficking of APP to the cell surface, where APP usually interacts with ferroportin (FPN) to facilitate the export of iron
A selective deficit in LTD but not in long-term potentiation (LTP) was observed in the CA1 region of the hippocampus in tau-knockout mice in vivo and ex vivo
In addition, tau may interact with actin to induce aligned bundles of actin filaments, thus modifying the organization of the cytoskeleton network
The reduction of tau levels in the brain causes dementia lacking distinctive histopathology (DLDH), the most common pathological variant of sporadic FTD
In AD and other tauopathies, the increase in dendritic tau levels is one of the first and most overt pathological abnormalities
In addition, dendritic tau could serve as a protein scaffold to deliver the kinase FYN to postsynaptic sites, where FYN phosphorylates subunit 2 of the NMDA receptor (NR2B; also known as GluN2B), resulting in the stabilization of the interaction of this receptor interaction with postsynaptic density protein 95 (PSD95; also known as DLG4), potentiating glutamatergic signalling and thereby enhancing Aβ toxicity.
In the human brain, tau can be cleaved behind Thr123, generating an N‑terminally truncated, tau124–441 fragment. This fragment exhibits stronger affinity for microtubules than does full-length tau, presumably because the removal of the negatively charged N‑terminal domain enhances its binding to the negative surface of microtubules
Nevertheless, the interaction of tau with RNA may induce tau aggregation and thus contribute to neurodegeneration
It is worth noting that another non-coding miRNA, miR‑219, can bind directly to the 3ʹ untranslated region of tau mRNA and thereby repress tau synthesis at the post-transcriptional level, although it does not affect splicing of tau.
In addition, tau can be phosphorylated by tyrosine kinases such as the SRC family members LCK, SYK and FYN at Tyr18, and the ABL family members ARG and ABL1 at Tyr394 (REF. 45).
For instance, hyperphosphorylated tau can interact with JIP1 and thus impair the formation of kinesin complex
Notably, as aggregated tau in patients with a tauopathy or in transgenic mice invariably show hyperphosphorylation, and tau hyperphosphorylation precedes aggregation, phosphorylation has been assumed to drive tau aggregation
Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits.
In a Drosophila melanogaster model of tauopathy, the hyperphosphorylation of tau led to the abnormal alignment and accumulation of F‑actin filaments, and thereby induced neurodegeneration
For instance, miR‑132, which is downregulated in PSP, reduces 4R tau expression in mouse neuroblastoma cells.
Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others
For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules
The two short hexapeptide motifs VQIINK and VQIVYK at the beginning of R2 and R3, respectively, show propensity for forming β‑sheet structures and are essential for tau aggregation, even though they comprise only a tiny fraction of the sequence
Disruption of these motifs (for example, by Pro mutations) abrogates the tendency for tau to aggregate; by contrast, strengthening the β‑structure with certain mutations (for instance, ΔK280 or P301L) accelerates tau aggregation both in vitro and in vivo
The motif VQIVYK has been shown to be sufficient to form fibrils composed of steric ‘zippers’ formed by two tightly interdigitated β‑sheets.
For instance, the phosphorylation of tau at Ser422 inhibits the cleavage of tau by caspase 3 at Asp421
In human AD brains and in the Tg4510 tauopathy mouse model, full-length tau is cleaved by caspase 3 behind Asp421 to generate tau1–421, which is prone to aggregation and subsequent formation of NFTs
Tau can be acetylated by the P300 acetyltransferase or by CREB-binding protein at several Lys residues in the flanking region or the repeat domain, and deacetylated at these sites by sirtuin 1 (SIRT1) and histone deacetylase 6 (HDAC6), respectively
In a cellular model of tauopathy, cells expressing the ΔK280 repeat-domain-mutant tau show tau aggregation that depends on the stepwise proteolysis of the N‑terminal domain by a thrombin-like protease and of the C‑terminal domain by cathepsin L, generating a fragment (F3) that leads to robust aggregation in cell and animal models
Notably, two proteins — 14‑3‑3ζ and immunophilin (also known as FKBP52 or FKBP4) — have also been shown to induce aggregation of recombinant tau in vitro, presumably by stabilizing an aggregation-prone conformation of tau.
Indeed, knockdown of FUS increases the expression of the 2N and 4R tau isoforms, providing a possible link between frontotemporal lobar degeneration-FUS (FTLDFUS; a subtype of FTD characterized by FUS inclusions in neurons and glia) and FTLD-tau (a tauopathy).
One of these fragments was identified as tau151–391, which is prone to aggregation, as rats transgenic for this fragment develop neurofibrillary pathology; the identity of the other fragment remains unclear
The truncation of tau at Asn368 has been observed in human AD brains and in a P301S mouse model of tauopathy, in which it leads to the generation of a tau1–368 fragment that is prone to aggregation and shows compromised microtubule-assembly activity, possibly contributing to tau aggregation and neurodegeneration.
For instance, a 20–22-kDa N‑terminal tau fragment (amino acids 26–230) was detected in an AD mouse model expressing a transgenic nerve growth factor (NGF)-specific antibody (AD11) and in the cerebrospinal fluid (CSF) of individuals with AD is neurotoxic in primary neurons
Truncation of tau prevents the formation of this structure and might thereby promote tau aggregation
Truncation of tau could generate tau fragments with a higher tendency for aggregation (see below), probably owing to the disruption of the paperclip structure of tau, as described above.
Truncated tau fragments that contain the repeat domain have a higher tendency for aggregation, probably owing to the disruption of the usual paperclip structure
In addition, the truncation of tau may result in tau fragments that induce neurodegeneration independently of tau aggregation.
Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353)
Recently, tau acetylation at Lys174 was identified in human AD brains as well.
By contrast, acetylation of tau at Lys280 has been detected in AD and other tauopathies, including AGD, tangle-predominant senile dementia (TPSD), PiD, FTDP‑17 and PSP, and is pathological
Non-enzymatic post-translational modifications, including glycation, deamidation and isomerization, are detected in PHF-tau but not in normal tau. All of these modifications may facilitate tau aggregation
In addition, glycation of tau may reduce the binding of tau to microtubules
The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies
The nitration of these Tyr residues alters the conformation of tau, reduces its binding to microtubules and, depending on the nitration sites, can promote or inhibit aggregation
In human AD brains, PHF-tau is methylated at fewer sites than is tau from normal human brains
Lysine methylation is another endogenous post-translational modification of tau in the human brain, and in vitro studies have shown that methylation of tau suppresses its aggregation
In human AD brains, but not in normal brains, tau is modified by N‑glycosylation, which is proposed to help to maintain and stabilize PHF structure
Furthermore, N‑glycosylation may facilitate tau hyperphosphorylation, as it suppresses the dephosphorylation and accelerates the phosphorylation of tau, probably because it changes the conformation of tau
In contrast to N‑glycosylation, O‑GlcNAcylation (a type of O‑glycosylation) of tau may protect it against phosphorylation, as it occupies the Ser or Thr residue of Ser‑Pro or Thr-Pro motifs
In addition, O‑GlcNAcylation of tau can suppress tau aggregation
In AD, the O‑GlcNAcylation of tau is reduced — an effect that might contribute to the hyperphosphorylation and aggregation of tau
In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule.
This view is supported by a recent study showing that tau in a normal mouse brain is phosphorylated at many sites that were previously found to be phosphorylated in tau from the brains of patients with AD.
The phosphorylation of tau appears to alter its association with actin, as tau phosphorylated at the KXGS motifs tends to colocalize with actin filaments in growth cones during development and in rod-like inclusions of cofilin and actin
In addition, phosphorylation of Ser214 and Thr231 in the flanking region of tau can trigger the detachment of tau from microtubules, whereas phosphorylation at other Thr-Pro or Ser-Pro motifs in the flanking region has only a weak influence on tau–microtubule binding
In a line of the JNPL3 tauopathy mouse model, which expresses human 0N4R tau bearing the missense P301L mutation, the overall increase in Tyr phosphorylation of tau correlated with the formation of tau aggregates, suggesting that overall Tyr phosphorylation might contribute to tau aggregation
In familial tauopathies, the mutation of MAPT seems to be the cause of tau aggregation, but in sporadic tauopathies (such as AD), the trigger of tau pathology is unclear.
Interestingly, the PSP-associated tau mutation A152T is localized far away from the repeat domain but still decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently
In addition, this A152T tau enhances the formation of oligomers but not fibres
Some tau mutations (such as A152T and R5H) may cause loss of tau function as well (as discussed above)
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation
Another mutation (R5H or R5L) outside the microtubule-binding domain disrupts the binding of tau to the p150 subunit of the dynactin complex — an essential cofactor for the microtubule motor dynein —thereby possibly interfering with general axonal transport
However, there are also other mutations (such as ΔK280, L266V and G272V) that inhibit the inclusion of E10 and thus reduce the 4R-to-3R ratio
Remarkably, in two regulatable transgenic mouse models expressing human tau with the P301L mutation (rTg4510) or expressing the repeat domain of tau with the ΔK280 mutation, switching off tau expression improved memory impairment even though NFTs remained, clearly showing that tau aggregates are not sufficient for neurodegeneration and the cognitive effects that are typically observed in these models
The pro-aggregant mouse lines developed AD‑like features (including missorting of tau into the somatodendritic compartment, tau conformational changes, tau hyperphosphorylation, NFTs and cognitive deficits), whereas the anti-aggregant lines show almost no pathology
Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau
Among them, PP2A is the main phosphatase:it accounts for ~70% of the human brain tau phosphatase activity, and its activity is reduced in the AD brain (by ~20% and ~40% in the grey and white matter, respectively)
Intriguingly, SRSF2 levels are increased in the brains of individuals with PSP.
Acetylation at Lys259, Lys290, Lys321 or Lys353 within the KXGS motifs occurs in normal tau, and is reduced in brains of individuals with AD and of rTg4510 transgenic mice
The truncation of tau occurs in AD and in other tauopathies
Notably, this accumulation of iron was observed in the brain regions with reduced soluble tau levels, such as the cortex in AD, the substantia nigra in PD and various brain regions in several other tauopathies
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.