Affinage

MAPT

Microtubule-associated protein tau · UniProt P10636

Length
758 aa
Mass
78.9 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPT encodes tau, a microtubule-associated protein whose primary physiological role is to bind and stabilize microtubules and regulate microtubule dynamic instability through its repeat-domain interactions (PMID:11756436, PMID:16495230, PMID:30587819). In the intracellular environment tau associates predominantly with microtubules via its MT-binding repeats, and disease-associated phosphorylation is rapidly reversed by cellular activity (PMID:30587819). Tau also performs nuclear functions, localizing to chromatin and regulating glutamatergic synaptic gene expression such as VGluT1 (PMID:30664870), and binding linker and nucleosomal DNA to drive chromatin compaction and protect DNA, interactions disrupted by hyperphosphorylation (PMID:38429335). FTDP-17 missense mutations and isoform-shifting mutations act largely through loss of microtubule regulatory function or by shifting the 3R:4R isoform ratio, with several mutations additionally promoting filament assembly as a gain of toxic function (PMID:9836646, PMID:10899436, PMID:16495230); isoform composition itself dictates filament morphology and disease identity, with all six isoforms in AD, 4R tau in CBD/PSP, and 3R tau in Pick's disease (PMID:10517507). Post-translational modifications govern tau behavior: acetylation by p300 and acetylmimetics at KXGS motifs suppress phase separation and aggregation while impairing microtubule binding (PMID:29734651, PMID:34426645), and kinases including GSK3, TTBK1, and CDK5 drive pathogenic hyperphosphorylation linked to metabolic stress and neurodegeneration (PMID:23036024, PMID:24808823). Tau undergoes liquid-liquid phase separation, which the RNA-binding protein TIA1 promotes in the presence of RNA to generate especially toxic oligomers (PMID:33619090). Pathologically, tau adopts distinct seed-competent monomer conformations that encode separate tauopathy strains (PMID:30526844); oligomers inhibit fast axonal transport through an N-terminal phosphatase-activation domain (PMID:22817713) and propagate trans-synaptically in an activity-dependent manner (PMID:27322420, PMID:31273083), with cell-type-specific glial transmission mechanisms (PMID:31826239). Tau is secreted via a Rab7A-dependent late endosomal route (PMID:28222213) and cleared by glymphatic (AQP4-dependent) drainage and the autophagy-lysosome pathway facilitated by BAG3/SYNPO and retromer VPS35 (PMID:35212707, PMID:30744518, PMID:32960680); endocytosed fibrils damage lysosomal membranes and nucleate cytosolic seeding at those membranes (PMID:38781206). Additional binding partners CAPON and G3BP2 modulate tau aggregation and toxicity, with G3BP2 protecting tau by masking its microtubule-binding region (PMID:31160584, PMID:37385246).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1998 High

    Established that FTDP-17 mutations cause disease by impairing tau's core microtubule-binding and assembly-promoting function, defining a loss-of-function axis for tau pathogenesis.

    Evidence Microtubule binding/assembly assays with recombinant mutant tau plus patient brain biochemistry

    PMID:9836646

    Open questions at the time
    • Did not establish whether loss of MT function alone is sufficient for neurodegeneration
    • Did not resolve the gain-of-function aggregation contribution
  2. 1999 High

    Showed that isoform composition determines tauopathy-specific filament morphology, linking the 3R:4R balance to distinct diseases.

    Evidence Biochemical fractionation and immunoblotting of insoluble tau across AD, CBD, PSP, and Pick's disease brains

    PMID:10517507

    Open questions at the time
    • Did not define the structural basis of isoform-specific assembly
    • Correlative across cohorts, not causal
  3. 1999 Medium

    Indicated that some FTDP-17 mutations alter tau proteolytic clearance, introducing degradation resistance as a possible pathogenic mechanism.

    Evidence In vitro calpain I digestion of recombinant mutant tau

    PMID:10561502

    Open questions at the time
    • Single in vitro proteolysis assay, single lab
    • Cellular relevance of calpain cleavage site accessibility not tested
  4. 2000 High

    Unified the loss-of-function and gain-of-toxic-function views by showing mutations either reduce MT interaction or shift toward 4R tau while several also stimulate filament formation.

    Evidence In vitro MT binding, heparin-induced filament assembly, and isoform ratio analysis

    PMID:10899436

    Open questions at the time
    • Heparin-induced assembly is non-physiological
    • Relative contribution of each mechanism in vivo unresolved
  5. 2001 High

    Confirmed in an intact-cell functional assay that most FTDP-17 mutants lose microtubule-regulatory activity, with mutation-specific exceptions (R406W near-normal, S305N hyperactive).

    Evidence Xenopus oocyte maturation assay with microinjected recombinant tau

    PMID:11756436

    Open questions at the time
    • Oocyte maturation is an indirect proxy for neuronal MT function
    • Did not address aggregation
  6. 2006 High

    Directly demonstrated in living cells that FTDP-17 mutations impair tau regulation of microtubule dynamic instability, solidifying the loss-of-function model.

    Evidence Live-cell imaging of individual microtubule dynamics after recombinant tau microinjection

    PMID:16495230

    Open questions at the time
    • Non-neuronal cell context
    • Did not connect dynamics defect to downstream neuronal phenotype
  7. 2013 High

    Identified the N-terminal phosphatase-activation domain (PAD) as the element by which tau oligomers, but not monomers, inhibit fast axonal transport, defining a discrete toxic mechanism reversible by Hsp70.

    Evidence Squid axoplasm transport assay with monomer/oligomer and PAD-deletion constructs, plus Hsp70 rescue

    PMID:22817713

    Open questions at the time
    • Invertebrate axoplasm system
    • PAD-dependent phosphatase activation not mapped to specific kinase/motor steps in mammalian neurons
  8. 2013 Medium

    Linked metabolic stress to tau hyperphosphorylation by showing hypoglycemia activates AMPK-Akt-GSK3 signaling to phosphorylate tau at disease sites.

    Evidence Glucose deprivation in N2a cells and ICV streptozotocin in rat hippocampus with phospho-specific blotting

    PMID:23036024

    Open questions at the time
    • Single lab
    • Causal link from GSK3 activity to tau pathology not established by intervention
  9. 2014 Medium

    Established TTBK1 as a direct tau kinase that also activates CDK5 and accelerates tau pathology in vivo, adding a kinase node to tau hyperphosphorylation.

    Evidence In vitro kinase assay, TTBK1×P301L transgenic cross, in vitro axonal degeneration

    PMID:24808823

    Open questions at the time
    • Single lab
    • TTBK1 overexpression may not reflect endogenous activity levels
  10. 2016 High

    Demonstrated that neuronal activity drives tau release and trans-synaptic transfer, providing a physiological trigger for pathological spread.

    Evidence Optogenetic and chemogenetic stimulation in vitro and in vivo with conditioned-medium transfer

    PMID:27322420

    Open questions at the time
    • Molecular release machinery not defined here
    • Did not establish which tau species transfers
  11. 2017 Medium

    Defined a Rab7A-dependent late endosomal route for tau secretion, identifying machinery for tau export.

    Evidence Rab7A deletion and dominant-negative/constitutively-active overexpression with secretion quantification and co-localization in neurons and HeLa cells

    PMID:28222213

    Open questions at the time
    • Single lab
    • Partial co-localization leaves other secretion routes open
  12. 2018 High

    Resolved how acetylation tunes tau, showing p300 hyperacetylation blocks LLPS and aggregation but causes loss of microtubule-stabilizing function.

    Evidence In vitro p300 acetylation with LLPS, ThT aggregation, and MT assembly readouts

    PMID:29734651

    Open questions at the time
    • In vitro only
    • Site-resolved acetylation effects not mapped here
  13. 2018 Medium

    Used in-cell NMR to show tau binds microtubules via its repeats in the native cellular environment and that disease phosphorylation is actively reversed, implying a cellular protection mechanism.

    Evidence In-cell NMR in HEK-293T with immunofluorescence and comparison to in vitro MT-bound spectra

    PMID:30587819

    Open questions at the time
    • Single lab/study
    • Non-neuronal cells; dephosphorylating enzymes not identified
  14. 2018 High

    Established that seed-competent tau monomer conformation encodes tauopathy strain identity, reframing strains as monomer-level conformational information.

    Evidence Monomer purification and inoculation into reporter cell lines and PS19 mice using human AD and CBD material

    PMID:30526844

    Open questions at the time
    • Structural basis of distinct monomer ensembles not determined
    • Mechanism converting monomer conformation to strain not resolved
  15. 2019 Medium

    Identified nuclear/chromatin-bound tau as a regulator of glutamatergic synaptic gene expression (VGluT1) impaired by P301L, defining a nuclear loss-of-function mechanism.

    Evidence Subcellular fractionation, MT-detachment/overexpression, qRT-PCR with P301L comparison

    PMID:30664870

    Open questions at the time
    • Mechanism of tau-driven transcriptional regulation unclear
    • Single lab
  16. 2019 High

    Identified CAPON as a tau-binding protein whose levels drive phosphorylation, oligomerization, and caspase-3-dependent neuronal death, with deficiency ameliorating pathology.

    Evidence IP/LC-MS interactome plus CAPON overexpression and knockout in MAPT knock-in mice

    PMID:31160584

    Open questions at the time
    • Direct vs indirect binding interface not mapped
    • Mechanism linking CAPON to tau phosphorylation unresolved
  17. 2019 High

    Showed humanization of tau accelerates seeded propagation and that human pathological tau seeds human tau more efficiently, revealing species-specific seeding determinants.

    Evidence Humanized MAPT knock-in mice injected with AD brain-derived tau seeds

    PMID:31273083

    Open questions at the time
    • Sequence determinants of species specificity not pinpointed
    • Did not resolve which isoforms drive efficiency
  18. 2019 Medium

    Established BAG3/SYNPO-mediated autophagic clearance of phospho-Ser262 tau in post-synaptic compartments, linking autophagosome-lysosome fusion to tau homeostasis.

    Evidence shRNA knockdown of BAG3 and SYNPO in primary neurons with autophagy flux and co-localization assays

    PMID:30744518

    Open questions at the time
    • Single lab
    • Selectivity for p-Ser262 tau over other species not fully defined
  19. 2020 High

    Revealed cell-type-specific glial tau transmission: oligodendroglial tau spreads independently of neurons whereas astrocytic tau requires neuronal tau.

    Evidence Neuronal tau knockdown mice injected with CBD/PSP lysates, tracked by immunohistochemistry

    PMID:31826239

    Open questions at the time
    • Molecular basis of glial uptake/spread not defined
    • Single lab
  20. 2020 Medium

    Established the autophagy-lysosome axis as the primary route for clearing aggregated tau, with retromer VPS35 controlling autophagy resolution.

    Evidence VPS35 knockdown/overexpression and chemical autophagy modulation in cell models with aggregate quantification

    PMID:32960680

    Open questions at the time
    • Cell-model only
    • Mechanistic link from retromer to autophagy resolution not detailed
  21. 2021 High

    Showed TIA1 directly drives physiological-concentration tau phase separation with RNA, generating oligomers more toxic than other aggregation routes, connecting RNP biology to tau toxicity.

    Evidence In vitro phase separation with purified tau, RNA, and TIA1 plus comparative toxicity assays

    PMID:33619090

    Open questions at the time
    • In vitro reconstitution; cellular validation limited
    • Toxic oligomer species not structurally defined
  22. 2021 Medium

    Showed KXGS-motif acetylmimetics inhibit seeded and intrinsic aggregation and alter tau conformation while reducing MT binding, dissecting site-specific acetylation effects.

    Evidence HEK293T aggregation and MT binding assays with site-directed acetylmimetic mutants and ThS staining

    PMID:34426645

    Open questions at the time
    • Acetylmimetics approximate but do not equal native acetylation
    • Single lab
  23. 2022 High

    Established AQP4-dependent glymphatic clearance as an in vivo route eliminating extracellular tau to CSF and lymph nodes, with loss exacerbating tau pathology.

    Evidence AQP4 knockout in P301S mice with tau tracking in CSF/ISF/lymph nodes and pathology readouts

    PMID:35212707

    Open questions at the time
    • Did not define molecular form of tau cleared
    • Glymphatic vs cellular clearance contributions not partitioned
  24. 2023 High

    Identified G3BP2 as a direct tau partner that suppresses aggregation by masking the microtubule-binding region, with loss elevating tau pathology in human neurons and organoids.

    Evidence Co-IP, MTBR mapping, G3BP2 knockdown in iPSC neurons/organoids, in vitro aggregation, human tauopathy brain analysis

    PMID:37385246

    Open questions at the time
    • Structural detail of MTBR masking not resolved
    • Regulation of G3BP2-tau interaction in disease unclear
  25. 2024 High

    Demonstrated that tau binds DNA, mononucleosomes, and nucleosome arrays via LLPS to compact chromatin and protect DNA, with hyperphosphorylation disrupting these chromatin functions.

    Evidence In vitro LLPS, DNA protection/digestion, chromatin compaction, enzymatic phosphorylation, and NMR/biophysics

    PMID:38429335

    Open questions at the time
    • In vitro reconstitution; in vivo chromatin role not established
    • Genomic targets of nuclear tau not mapped
  26. 2024 High

    Showed endocytosed tau fibrils damage lysosomal membranes and nucleate cytosolic seeding at those membranes, coupling lysosomal escape to seeding.

    Evidence Live-cell and STORM imaging with ESCRT/Galectin-3 markers in primary astrocytes and neurons

    PMID:38781206

    Open questions at the time
    • Molecular trigger of membrane permeabilization not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How tau's physiological microtubule, nuclear/chromatin, and phase-separation functions are coordinately lost and converted into strain-specific seed-competent aggregates in disease remains unresolved at the structural and pathway-integration level.
  • No structural mechanism linking monomer conformational ensembles to specific clinical strains
  • Integration of secretion, glymphatic, and autophagic clearance routes in vivo not quantified
  • Causal hierarchy among phosphorylation, acetylation, and aggregation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005576 extracellular region 2 GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 2 R-HSA-4839726 Chromatin organization 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
BAG3CAPONG3BP2RAB7ASYNPOTIA1TTBK1VPS35

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 FTDP-17 missense mutations in tau (e.g., G272V, P301L, V337M, R406W, E10+16) reduce the ability of recombinant tau to bind microtubules and promote microtubule assembly, with different mutations differentially altering biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins (microtubule binding and assembly assays); biochemical analysis of soluble and insoluble tau from FTDP-17 patient brains Science High 9836646
2000 FTDP-17 mutations either reduce tau's ability to interact with microtubules or increase production of tau isoforms with four microtubule-binding repeats (4R tau); several missense mutations also stimulate heparin-induced tau filament formation in vitro, suggesting a gain of toxic function. In vitro microtubule binding assays, in vitro tau filament assembly assays with heparin, isoform ratio analysis Biochimica et biophysica acta High 10899436
1999 3R and 4R tau isoforms aggregate into distinct filament morphologies in different tauopathies: all six isoforms in Alzheimer's disease PHFs; only 4R tau in CBD and PSP (twisted/straight filaments); only 3R tau in Pick's disease (random coiled filaments), demonstrating isoform-specific filament assembly. Biochemical fractionation and immunoblotting of insoluble tau from tauopathy brains Brain pathology High 10517507
2001 Using Xenopus oocyte maturation as a microtubule function assay, wild-type four-repeat tau inhibits maturation concentration-dependently while three-repeat tau has no effect. Five FTDP-17 mutants (G272V, ΔK280, P301L, P301S, V337M) failed to inhibit maturation, demonstrating reduced microtubule interaction; R406W behaved nearly like wild-type; S305N inhibited maturation more strongly than wild-type. Xenopus oocyte maturation assay with microinjected recombinant tau proteins The Journal of biological chemistry High 11756436
2006 FTDP-17 mutations G272V, ΔK280, and P301L markedly reduce tau's ability to regulate microtubule dynamic instability in living cells, while R406W (outside the microtubule-binding domain) does not significantly alter this regulation, consistent with a loss-of-function mechanism for most tau missense mutations. Microinjection of recombinant tau into cells expressing fluorescent tubulin; live-cell imaging of individual microtubule dynamic instability The Journal of biological chemistry High 16495230
1999 FTDP-17 mutants V337M and R406W are less susceptible than P301L or wild-type tau to degradation by calpain I, with differences in accessibility of a cleavage site ~100 amino acids from the C-terminus, suggesting some FTDP-17 pathogenesis involves reduced proteolytic tau clearance. In vitro calpain I digestion assay of recombinant mutant tau proteins FEBS letters Medium 10561502
2016 Increased neuronal activity (optogenetic and chemogenetic stimulation) stimulates tau release in vitro and enhances tau pathology in vivo; physiological tau released from donor cells can transfer to recipient cells via the extracellular space. Optogenetic and chemogenetic approaches in vitro and in vivo; conditioned medium transfer assay Nature neuroscience High 27322420
2017 Rab7A regulates tau secretion: deletion of Rab7A decreases tau secretion, while overexpression of dominant-negative Rab7A decreases and constitutively active Rab7A increases tau secretion. Partial co-localization of tau with Rab7A-positive late endosomal structures implicates late endosomes in tau secretion. Rab7A deletion and dominant-negative/constitutively active overexpression in cortical neurons and HeLa cells; tau secretion quantification; co-localization imaging Journal of neurochemistry Medium 28222213
2019 CAPON (carboxy-terminal PDZ ligand of nNOS) is a novel tau-binding protein identified by immunoprecipitation/LC-MS. CAPON overexpression induces higher levels of phosphorylated, oligomerized, and insoluble tau and causes caspase3-dependent neuronal death; CAPON deficiency ameliorates AD-related tau pathology. Immunoprecipitation/LC-MS tau interactome screen; CAPON overexpression and knockout in MAPT knock-in mice; biochemical fractionation; caspase3 assay Nature communications High 31160584
2021 TIA1 (RNA-binding protein) directly interacts with tau and drives its phase separation at physiological concentrations in the presence of RNA, without artificial crowding agents. Tau oligomers generated during TIA1 co-partitioning are significantly more toxic than aggregates formed with RNA alone or with crowding agents. In vitro phase separation assays with purified tau, RNA, and TIA1; toxicity assays comparing oligomers from different conditions Proceedings of the National Academy of Sciences of the United States of America High 33619090
2018 Hyperacetylation of tau by p300 histone acetyltransferase disfavors liquid-liquid phase separation (LLPS) of tau, inhibits heparin-induced aggregation, and impedes LLPS-initiated microtubule assembly, indicating that acetylation prevents LLPS-dependent aggregation but also causes loss-of-function in microtubule stabilization. In vitro acetylation by p300; LLPS assays; thioflavin T aggregation assay; microtubule assembly assay International journal of molecular sciences High 29734651
2022 Aquaporin-4 (AQP4)-driven glymphatic clearance facilitates elimination of extracellular tau from brain to CSF and cervical lymph nodes. AQP4 deletion elevates tau in CSF and markedly exacerbates phosphorylated tau deposition and neurodegeneration in P301S tau transgenic mice. AQP4 knockout in P301S tau transgenic mice; tau quantification in CSF, interstitial fluid, and lymph nodes; immunohistochemistry for tau pathology and neurodegeneration markers The Journal of experimental medicine High 35212707
2019 In humanized MAPT knock-in mice expressing all six human tau isoforms, tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau, and pathological human tau interacts more efficiently with human tau than with murine tau, revealing species-specific differences in tau seeding. Homologous recombination knock-in; injection of AD brain-derived tau seeds; histological analysis of tau propagation The Journal of biological chemistry High 31273083
2020 Oligodendroglial tau pathology propagates along white matter tracts independently of neuronal axons and results in oligodendrocyte cell loss. In contrast, astrocytic tau pathology requires neuronal tau for propagation, revealing cell-type-specific mechanisms of glial tau transmission. Neuronal tau knockdown mouse model; injection of CBD/PSP tau lysates; immunohistochemistry tracking glial tau spread and oligodendrocyte loss The Journal of experimental medicine High 31826239
2019 BAG3, in cooperation with SYNPO (synaptopodin), facilitates autophagic clearance of phosphorylated tau (p-Ser262) in neuronal processes. Loss of either BAG3 or SYNPO impedes autophagosome-lysosome fusion predominantly in the post-synaptic compartment, leading to accumulation of p-Ser262 tau. shRNA knockdown of BAG3 and SYNPO in primary neurons; autophagy flux assay; immunofluorescence co-localization; biochemical fractionation Autophagy Medium 30744518
2020 Retromer component VPS35 depletion blocks autophagy resolution and causes marked accumulation of cytoplasmic tau aggregates; VPS35 overexpression has the opposite effect. The autophagy-lysosome axis is identified as the primary mode for clearance of aggregated tau species. Chemical and genetic (VPS35 knockdown/overexpression) approaches in cell models; tau aggregate quantification Autophagy Medium 32960680
2013 Tau oligomers (but not monomers) inhibit anterograde fast axonal transport (FAT) in a squid axoplasm assay; this inhibition requires a small N-terminal stretch termed the phosphatase-activation domain (PAD). Hsp70 preferentially binds tau oligomers and prevents their FAT inhibition. Squid axoplasm assay with monomeric vs. oligomeric/filamentous tau; PAD-deleted tau constructs; Hsp70 co-incubation Biochemical Society transactions High 22817713
2018 In-cell NMR in HEK-293T cells shows tau predominantly binds microtubules via its MT-binding repeats in the intracellular environment. Disease-associated phosphorylation of tau is rapidly dephosphorylated upon delivery into cells, suggesting an active cellular protection mechanism. In-cell NMR spectroscopy; immunofluorescence co-localization; comparison of in-cell spectrum to in vitro MT-bound tau spectrum International journal of molecular sciences Medium 30587819
2019 Nuclear tau localizes to soluble and chromatin-bound fractions. Tau overexpression or detachment from microtubules increases VGluT1 gene expression. The FTDP-17 P301L mutation impairs this nuclear tau function, representing a loss-of-function mechanism affecting glutamatergic synaptic gene regulation. Subcellular fractionation; overexpression and microtubule-detachment experiments; qRT-PCR and western blot for VGluT1; P301L mutation comparison Journal of molecular biology Medium 30664870
2024 Endocytosed tau fibrils accumulate in lysosomes of primary astrocytes and neurons, causing lysosomal swelling, deacidification, and ESCRT protein recruitment (but not Galectin-3) consistent with nanoscale membrane damage. Nucleation of cytosolic tau occurs predominantly at the lysosomal membrane, coupling lysosomal escape to cytosolic seeding. Live-cell imaging; STORM superresolution microscopy; ESCRT/Galectin-3 marker recruitment assays in primary cells Proceedings of the National Academy of Sciences of the United States of America High 38781206
2018 Seed-competent tau monomer (Ms) adopts multiple stable conformational ensembles that each encode distinct tau strains. Ms from AD brain encodes a single strain; Ms from CBD brain encodes three sub-strains that each re-establish all three upon inoculation into cells. Tau monomer conformation thus determines strain identity. Tau monomer purification and inoculation into tau-reporter cell lines (DS9, DS10); inoculation into PS19 tauopathy mice; neuropathological readout eLife High 30526844
2021 Acetylmimetic mutations at K321Q and K353Q (KXGS motifs) in tau strongly inhibit prion-like seeded aggregation and intrinsic aggregation of pathogenic P301L/S320F tau double mutant, and alter tau conformational structure to impair Thioflavin S binding, while acetylmimetics at all KXGS sites decrease tau-microtubule interactions. HEK293T cell-based tau aggregation assay; microtubule binding assay; Thioflavin S staining; site-directed mutagenesis Scientific reports Medium 34426645
2024 Tau undergoes liquid-liquid phase separation (LLPS) with DNA, mononucleosomes, and reconstituted nucleosome arrays; low concentrations of tau promote chromatin compaction and protect DNA from digestion. These interactions are driven by tau's binding to linker and nucleosomal DNA and are disrupted by tau hyperphosphorylation. In vitro LLPS assays; DNA protection/digestion assays; chromatin compaction assays; phosphorylation with kinases; NMR and biophysical characterization Communications biology High 38429335
2023 G3BP2, a core stress granule component, directly interacts with tau and inhibits tau aggregation by masking the microtubule-binding region (MTBR) of tau. Loss of G3BP2 in human neurons and brain organoids significantly elevates tau pathology; G3BP2-tau interaction is increased in multiple human tauopathies independent of NFT formation. Co-immunoprecipitation; G3BP2 knockdown in iPSC-derived neurons and brain organoids; in vitro aggregation assay; MTBR mapping; human tauopathy brain analysis Neuron High 37385246
2013 Hypoglycemia activates the AMPK-Akt-GSK3 pathway in neurons, leading to increased GSK3α/β activity and tau hyperphosphorylation at Ser262 and Ser396, both in differentiated N2a cells and in rat hippocampus following intracerebroventricular streptozotocin injection. Cell culture glucose deprivation; in vivo intracerebroventricular STZ injection; western blot for phospho-tau, phospho-GSK3, phospho-Akt, phospho-AMPK Current Alzheimer research Medium 23036024
2014 Tau-tubulin kinase 1 (TTBK1) directly phosphorylates tau, especially at Ser422, and activates CDK5. TTBK1 transgenic mice crossed with P301L tau mice show accelerated tau accumulation and neuroinflammation, and TTBK1 overexpression induces axonal degeneration in vitro. In vitro kinase assay; TTBK1 transgenic mouse cross with tau mutant mice; in vitro axonal degeneration assay Frontiers in molecular neuroscience Medium 24808823

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science (New York, N.Y.) 809 9836646
2011 The many faces of tau. Neuron 682 21555069
2016 Neuronal activity enhances tau propagation and tau pathology in vivo. Nature neuroscience 656 27322420
2016 Tau and tauopathies. Brain research bulletin 461 27615390
2011 Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). Journal of molecular neuroscience : MN 310 21720721
1999 Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. Brain pathology (Zurich, Switzerland) 305 10517507
2021 Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation. Frontiers in neurology 279 33488497
2004 The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Human mutation 277 15365985
2019 A walk through tau therapeutic strategies. Acta neuropathologica communications 214 30767766
2022 Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. The Journal of experimental medicine 208 35212707
2012 Tau oligomers and tau toxicity in neurodegenerative disease. Biochemical Society transactions 182 22817713
2018 Biomarkers for tau pathology. Molecular and cellular neurosciences 175 30529601
2018 Tau in neurodegenerative disease. Annals of translational medicine 164 29951497
2019 Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. The Journal of biological chemistry 161 31273083
2017 Propagation of Tau aggregates. Molecular brain 156 28558799
2002 Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends in molecular medicine 150 12470988
2010 Tau protein and tau aggregation inhibitors. Neuropharmacology 148 20149808
2018 Acetylation Disfavors Tau Phase Separation. International journal of molecular sciences 146 29734651
2018 It's all about tau. Progress in neurobiology 143 30605723
2004 Tau protein and neurodegeneration. Seminars in cell & developmental biology 135 15036206
2012 Tau and tauopathies. Progress in molecular biology and translational science 133 22482453
2000 Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. Biochimica et biophysica acta 131 10899436
2016 Tau Biology and Tau-Directed Therapies for Alzheimer's Disease. Drugs 126 26729186
2021 TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau. Proceedings of the National Academy of Sciences of the United States of America 122 33619090
2008 Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Archives of neurology 122 18413467
2018 Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain : a journal of neurology 118 29253099
2021 Tau Oligomers Neurotoxicity. Life (Basel, Switzerland) 113 33418848
2020 Toxic tau: structural origins of tau aggregation in Alzheimer's disease. Neural regeneration research 112 31997800
2016 Tau Structures. Frontiers in aging neuroscience 109 27877124
2021 Tau strains shape disease. Acta neuropathologica 107 33830330
2017 Amyloidogenesis of Tau protein. Protein science : a publication of the Protein Society 106 28833749
2014 Acetylation: a new key to unlock tau's role in neurodegeneration. Alzheimer's research & therapy 105 25031639
2005 Pathways of tau fibrillization. Biochimica et biophysica acta 103 15615636
2000 Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 103 10983715
2002 Tau and axonopathy in neurodegenerative disorders. Neuromolecular medicine 102 12428808
2018 Tau filaments in neurodegenerative diseases. FEBS letters 100 29790176
2010 Proteolytic processing of tau. Biochemical Society transactions 100 20658984
2015 Tau imaging in neurodegenerative diseases. European journal of nuclear medicine and molecular imaging 96 26572762
2001 Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 96 11402146
2010 From tau phosphorylation to tau aggregation: what about neuronal death? Biochemical Society transactions 88 20658986
2020 Resurrecting the Mysteries of Big Tau. Trends in neurosciences 87 32434664
2000 Untangling tau-related dementia. Human molecular genetics 87 10767321
2018 Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration. Frontiers in molecular neuroscience 86 30174587
2022 Tau Isoforms: Gaining Insight into MAPT Alternative Splicing. International journal of molecular sciences 85 36499709
2020 Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. The Journal of experimental medicine 81 31826239
2019 Tau binding protein CAPON induces tau aggregation and neurodegeneration. Nature communications 81 31160584
2006 FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. The Journal of biological chemistry 81 16495230
2013 Anesthesia and tau pathology. Progress in neuro-psychopharmacology & biological psychiatry 79 23535147
2019 BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes. Autophagy 77 30744518
2013 What Renders TAU Toxic. Frontiers in neurology 71 23772223
2008 Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration. Current Alzheimer research 68 19075586
2013 Characteristics of tau oligomers. Frontiers in neurology 67 23882258
2013 Tauopathies and tau oligomers. Journal of Alzheimer's disease : JAD 66 23948895
2018 Tau monomer encodes strains. eLife 62 30526844
2002 Tau, where are we now? Journal of Alzheimer's disease : JAD 61 12446970
2021 Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration. Frontiers in neuroscience 60 34744602
2024 Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes. Proceedings of the National Academy of Sciences of the United States of America 58 38781206
2020 Bacterial DNA promotes Tau aggregation. Scientific reports 57 32047247
2014 Tau-tubulin kinase. Frontiers in molecular neuroscience 56 24808823
2021 Tau and MAPT genetics in tauopathies and synucleinopathies. Parkinsonism & related disorders 54 34593302
2015 The many faces of interferon tau. Amino acids 53 25557050
2017 Rab7A regulates tau secretion. Journal of neurochemistry 52 28222213
2010 Tau cleavage and tau aggregation in neurodegenerative disease. Biochemical Society transactions 51 20658996
2013 Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies. Neuropharmacology 48 24050961
2000 Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Their relevance for understanding the neurogenerative process. Annals of the New York Academy of Sciences 48 11193179
2015 Tau Immunotherapy. Neuro-degenerative diseases 47 26551002
2023 Tau and neurodegeneration. Cytoskeleton (Hoboken, N.J.) 45 38073060
2022 Tau Aggregation. Neuroscience 44 35525497
2013 Hypoglycemia induces tau hyperphosphorylation. Current Alzheimer research 43 23036024
1990 Tau protein and neurodegeneration. Molecular neurobiology 43 2135393
2001 Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation. The Journal of biological chemistry 41 11756436
1999 FTDP-17 tau mutations decrease the susceptibility of tau to calpain I digestion. FEBS letters 40 10561502
2008 Tau aggregates and tau pathology. Journal of Alzheimer's disease : JAD 39 18688097
2022 Tau Toxicity in Neurodegeneration. Molecular neurobiology 38 35359226
1999 Fibrillogenesis of tau: insights from tau missense mutations in FTDP-17. Brain pathology (Zurich, Switzerland) 38 10517508
2015 Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS chemical neuroscience 37 25822288
2015 TTBK2: a tau protein kinase beyond tau phosphorylation. BioMed research international 37 25950000
2006 Clinical-pathologic study of biomarkers in FTDP-17 (PPND family with N279K tau mutation). Parkinsonism & related disorders 36 17196872
2007 Tau and tauopathies. Neurology India 35 17272893
2019 14-3-3/Tau Interaction and Tau Amyloidogenesis. Journal of molecular neuroscience : MN 34 31062171
2024 Phosphorylation regulates tau's phase separation behavior and interactions with chromatin. Communications biology 33 38429335
2021 Tau internalization: A complex step in tau propagation. Ageing research reviews 33 33571704
2022 All the Tau We Cannot See. Annual review of medicine 32 36378913
2020 Retromer regulates the lysosomal clearance of MAPT/tau. Autophagy 31 32960680
2023 Tau, tau kinases, and tauopathies: An updated overview. BioFactors (Oxford, England) 29 36688478
2020 Red Ginseng Inhibits Tau Aggregation and Promotes Tau Dissociation In Vitro. Oxidative medicine and cellular longevity 28 32685100
2016 Pioglitazone prevents tau oligomerization. Biochemical and biophysical research communications 28 27543203
2021 Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau-microtubule interactions and inhibits aggregation. Scientific reports 27 34426645
2017 Tau-imaging in neurodegeneration. Methods (San Diego, Calif.) 27 28790016
2019 Tau Modulates VGluT1 Expression. Journal of molecular biology 26 30664870
2013 Tau aggregates as immunotherapeutic targets. Frontiers in bioscience (Scholar edition) 26 23277060
2017 The evolution of interferon-tau. Reproduction (Cambridge, England) 25 28982935
2003 Early and pre-symptomatic neuropsychological dysfunction in the PPND family with the N279K tau mutation. Parkinsonism & related disorders 25 12781592
2023 Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response. Scientific data 24 37730697
2019 Xanthohumol inhibits tau protein aggregation and protects cells against tau aggregates. Food & function 24 31793596
2013 Potential synergy between tau aggregation inhibitors and tau chaperone modulators. Alzheimer's research & therapy 24 24041111
2022 Reassessment of Neuronal Tau Distribution in Adult Human Brain and Implications for Tau Pathobiology. Acta neuropathologica communications 23 35765058
2018 In-Cell NMR Study of Tau and MARK2 Phosphorylated Tau. International journal of molecular sciences 23 30587819
2023 Increased G3BP2-Tau interaction in tauopathies is a natural defense against Tau aggregation. Neuron 22 37385246
2022 The Interplay between GSK3β and Tau Ser262 Phosphorylation during the Progression of Tau Pathology. International journal of molecular sciences 22 36232909

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