PubMed: 26631930

Tau in physiology and pathology.
Nature reviews. Neuroscience
Mandelkow E | Wang Y

Evidence 49ee9a57ab

In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration

Evidence 283fa5e918

This fragment was proposed to be generated by caspases (although not caspase 3).

Evidence 31ebebf08b

However, tau aggregates are also observed in the brains of some aged individuals with a condition known as primary age-related tauopathy (PART)

Evidence d0d42bc172

Tau aggregation decreases levels of soluble functional tau, which may result in microtubule disassembly as well

Evidence fb96895bd7

In the longer term, however, these tau aggregates may sequester other cell components, finally compromising neuronal functions

Evidence f5806bdefd

The interaction of tau with FYN may regulate the postsynaptic targeting of FYN, and thereby mediate Aβ‑induced excitotoxicity

Evidence 023530228d

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

Evidence 783de9e02b

Tau aggregation could be accelerated by cofactors such as polyanions that compensate for the repulsive positive charges of tau

Evidence 3bd4cc74d3

Conversely, tau aggregation can be induced in vitro efficiently by polyanionic cofactors, regardless of phosphorylation

Evidence f65ef3f56a

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

Evidence d4bfde45d0

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

Evidence 877665b9a4

Hyperphosphorylation, mutations and overexpression of tau can drive the mislocalization of tau into postsynaptic spines, resulting in synaptic dysfunction

Evidence 7e46ce4717

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD

Evidence 5483a09e92

This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation

Evidence 8a94382271

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.

Evidence f07f5b8197

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

Evidence d7d1f19dd7

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD.

Evidence 70b8759016

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).

Evidence 3981a2ccc5

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.

Evidence 640951edbb

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

Evidence be7079ff9f

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

Evidence b925089c0a

Tau is known to be ubiquitylated through Lys48 linkages by CHIP for proteasomal degradation

Evidence 574f9765c3

Notably, one study demonstrated that tau can also be ubiquitylated through Lys63 linkages by TNF receptor-associated factor 6 (TRAF6) — again, for proteasomal degradation

Evidence 9b8c65aa18

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

Evidence fa51443171

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

Evidence 9461ee525a

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).

Evidence f7b48fc3d0

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

Evidence 5ea554cb98

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)

Evidence 998f43257e

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

Evidence d9705bc890

Tau thereby stabilizes microtubules, promotes microtubule assembly and, in particular, regulates the dynamic instability of microtubules that allows reorganization of the cytoskeleton.

Evidence 5db4433848

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

Evidence 139067a53e

Notably, tau has intrinsic acetyltransferase activity and so can catalyse auto-acetylation at certain Lys sites, including Lys280

Evidence b765a5c5d9

First, hyperphosphorylation of tau might induce tau missorting from axons to the somatodendritic compartment, which can cause synaptic dysfunction

Evidence ce00749913

In human AD brains, the missorting of tau into dendrites represents one of the early signs of neurodegeneration

Evidence 38f49f7403

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.

Evidence 467532ffaf

In adult neurons, tau mainly distributes into axons, where it interacts with microtubules through the repeat-domain and flanking regions.

Evidence c442efd649

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

Evidence 8a7c86cdea

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

Evidence 8d0ecf51b4

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

Evidence ab3e13f173

These studies indicate that the endogenous tau plays a part in regulating neuronal activity

Evidence 8ad90d4782

Intraneuronal iron accumulation, neuronal loss in the substantia nigra and a severe decline in locomotor functions were observed in 12‑month-old tau-knockoutmice

Evidence e6881b23f9

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.

Evidence 941a6b9b3b

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

Evidence cfcad71abc

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

Evidence b6d083ce02

In addition, tau may interact with actin to induce aligned bundles of actin filaments, thus modifying the organization of the cytoskeleton network

Evidence b8a33d9719

The reduction of tau levels in the brain causes dementia lacking distinctive histopathology (DLDH), the most common pathological variant of sporadic FTD

Evidence ce1ae99b76

In AD and other tauopathies, the increase in dendritic tau levels is one of the first and most overt pathological abnormalities

Evidence 284c03faba

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.

Evidence a88eda92d2

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

Evidence 437ec0bc97

Nevertheless, the interaction of tau with RNA may induce tau aggregation and thus contribute to neurodegeneration

Evidence 07048241e5

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.

Evidence 4e7a52d496

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).

Evidence 2e62c4189b

For instance, hyperphosphorylated tau can interact with JIP1 and thus impair the formation of kinesin complex

Evidence a03afb06e6

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

Evidence efd966e889

Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits.

Evidence aff41e4b10

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

Evidence 60d3e17720

For instance, miR‑132, which is downregulated in PSP, reduces 4R tau expression in mouse neuroblastoma cells.

Evidence 44ff4dea64

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

Evidence 4b84bb5801

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

Evidence 29e75cd797

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

Evidence fd1326ada8

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

Evidence 9e5d9c3d3c

The motif VQIVYK has been shown to be sufficient to form fibrils composed of steric ‘zippers’ formed by two tightly interdigitated β‑sheets.

Evidence 27fb01e071

For instance, the phosphorylation of tau at Ser422 inhibits the cleavage of tau by caspase 3 at Asp421

Evidence a726f4c080

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

Evidence 6914457aae

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

Evidence 05278646fb

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

Evidence d6266fd050

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.

Evidence 00c96876ce

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).

Evidence b90207c2cc

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

Evidence 054d19ffd4

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.

Evidence 2cba670aeb

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

Evidence e2cfce4eb8

Truncation of tau prevents the formation of this structure and might thereby promote tau aggregation

Evidence e031dd630b

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.

Evidence 4a368728b9

Truncated tau fragments that contain the repeat domain have a higher tendency for aggregation, probably owing to the disruption of the usual paperclip structure

Evidence 3371f5a09f

In addition, the truncation of tau may result in tau fragments that induce neurodegeneration independently of tau aggregation.

Evidence c39cd5cf3d

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)

Evidence dc7c4926c5

Recently, tau acetylation at Lys174 was identified in human AD brains as well.

Evidence ca9032afb4

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

Evidence 4c6e0800af

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

Evidence 9746fbc788

In addition, glycation of tau may reduce the binding of tau to microtubules

Evidence 8a4b1bd175

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

Evidence 73fe9058a7

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

Evidence 62d5e3aff1

In human AD brains, PHF-tau is methylated at fewer sites than is tau from normal human brains

Evidence 2fc4759d7a

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

Evidence 2ad070e1fd

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

Evidence 224d9e0ab0

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

Evidence b7e94dbead

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

Evidence 1e060a373d

In addition, O‑GlcNAcylation of tau can suppress tau aggregation

Evidence 7e046f883d

In AD, the O‑GlcNAcylation of tau is reduced — an effect that might contribute to the hyperphosphorylation and aggregation of tau

Evidence 9f059f35ab

In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule.

Evidence bb7ed49c25

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.

Evidence b8edbafe2a

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

Evidence bbae16f517

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

Evidence 1e69b896c1

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

Evidence 1c1be63790

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.

Evidence c85bd960f2

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

Evidence 808079e22f

In addition, this A152T tau enhances the formation of oligomers but not fibres

Evidence f113be8dbd

Some tau mutations (such as A152T and R5H) may cause loss of tau function as well (as discussed above)

Evidence 8dfa70696d

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

Evidence a2646e0b4e

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

Evidence 451296b278

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

Evidence 9972b6a87c

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

Evidence bb252531be

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

Evidence 6b751bec36

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau

Evidence 6d59fd403f

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)

Evidence dfc6fdad0c

Intriguingly, SRSF2 levels are increased in the brains of individuals with PSP.

Evidence 784b18c85f

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

Evidence 8334f2407e

The truncation of tau occurs in AD and in other tauopathies

Evidence 77b0044e99

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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