CoChat
Sign Up
Cited by 63Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Open access
Yang, Jiakai, Zhi, Weijia, Wang, Lifeng·2024·Molecules
DOI 10.3390/molecules29122812PMC PMC11206543
Open this paper in CoChat — free account

Abstract

Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function. Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders. The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles. Therefore, studying the role of tau protein in neurodegenerative diseases and the mechanism of aberrant aggregation is important for understanding the mechanism of neurodegenerative diseases and finding therapeutic approaches. This review describes the possible mechanisms by which tau protein promotes neurodegenerative diseases, the post-translational modifications of tau protein and associated influencing factors, and the current status of drug discovery and development related to tau protein, which may contribute to the development of new therapeutic approaches to alleviate or treat neurodegenerative diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes tau protein biology, post-translational modifications, factors promoting tau hyperphosphorylation, and tau-targeted drug development in neurodegenerative diseases. It reports that no tau-targeted drug has been approved, though several candidates have shown biomarker or pathology effects in clinical trials without consistent cognitive benefit.

Key findings

  • Tau aggregates as neurofibrillary tangles in AD, FTD, PD, HD, and other tauopathies; hyperphosphorylation, acetylation, glycosylation, and methylation affect tau aggregation and toxicity. In AD, approximately 50 million people worldwide are affected, with approximately 10 million new cases each year, predicted to increase to 152 million by 2050. Tau has more than 80 phosphorylation sites; T50, T69, T181, and T205 are described as “master sites,” with GSK3β and p38a closely related to tau phosphorylation regulation.
  • Tau interacts with amyloid-β and α-synuclein; in PD, tau promotes α-synuclein aggregation and spreading, and tau-α-synuclein interactions influence α-synuclein pathology. In HD, reported tau alterations include increased total tau levels, an increased 4R-/3R-tau ratio, and post-translational modifications such as hyperphosphorylation or truncation.
  • Factors influencing tau hyperphosphorylation include dietary/lifestyle factors (sleep deprivation, high salt, high-fat diet, periodontitis/Porphyromonas gingivalis), genetic factors (MAPT with more than 40 known variants, ApoEε4, PSEN1/PSEN2, GRN), and environmental/chemical exposures (arsenic, zinc, iron, copper, anaesthetics such as propofol and sevoflurane).
  • Drug development: no tau-targeted drug has been approved. Lithium salts, tideglusib, saracatinib, nilotinib, sodium selenate, and LMTX failed to show cognitive benefit or did not affect tau in trials. AADvac1 produced antibodies in 95% of subjects in a phase 2 study and significantly reduced CSF pTau217 levels but showed no cognitive benefit. MAPTRx, an antisense oligonucleotide, reduced CSF tau concentrations by more than 50% on average 24 weeks after the last dose in patients with mild AD.

Methods

  • Design: narrative literature review; no systematic review methodology, search strategy, databases, or inclusion/exclusion criteria are stated in the paper.
  • Data or sample: published literature and clinical trial reports; no primary experimental data, patient cohort, or meta-analytic dataset are presented.
  • Main analysis: thematic synthesis of tau structure and function, post-translational modifications, disease associations, factors influencing tau hyperphosphorylation, and tau-targeted therapeutic strategies.

Limitations

  • Stated in the paper: tau is highly complex, with different splicing isoforms and post-translational modifications that affect its structure and function; various neurodegenerative diseases lead to abnormal tau aggregation through different genetic and environmental factors; treatment during the therapeutic window is important; tau-targeted therapies face problems including immune reactions, cytotoxicity, and other adverse effects.
  • Evident from the text: the review does not describe a systematic search, inclusion/exclusion criteria, or quality assessment, so selection bias is possible; it provides no quantitative meta-analysis. Some cited clinical trials had not published results at the time of writing (e.g., a curcumin phase 2 study due to be completed in 2020).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/molecules29122812

Cites

202 of 202 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 159 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    This was the first clinical attempt to use a gene-silencing-based drug for a dementia-related disease such as AD.

    “This was the first clinical attempt to use a gene-silencing-based drug for a dementia-related disease such as AD [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Mummery, 2023, Tau-targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer’s disease: A phase 1b, randomized, placebo-controlled trial, Nat. Med. source

      Not checked in the free run.

  • Premisecitation

    The actual role of tau in regulating microtubule stability in the axon is not to stabilise axonal microtubules, but rather to allow them to have long labile domains.

    “The actual role of tau in regulating microtubule stability in the axon is not to stabilise axonal microtubules, but rather to allow them to have long labile domains [16,17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Baas, 2019, Tau: It’s Not What You Think, Trends Cell Biol. source

      Not checked in the free run.

    • cites [17] Qiang, 2018, Tau Does Not Stabilize Axonal Microtubules but Rather Enables Them to Have Long Labile Domains, Curr. Biol. source

      Not checked in the free run.

  • Premisecitation

    In Alzheimer's disease, tau protein was found to be glycosylated and O-GlcNAcylated before becoming aberrantly phosphorylated and N-linked-glycosylated at the N410 site of the tau 2N4R heterodimer.

    “In AD, tau protein was found to be glycosylated and O-GlcNAcylated before becoming aberrantly phosphorylated and N-linked-glycosylated at the N410 site of the tau 2N4R heterodimer.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Haukedal, 2020, Implications of Glycosylation in Alzheimer’s Disease, Front. Neurosci. source

      Not checked in the free run.

  • Premisecitation

    NLRP3 inflammatory vesicles actively regulate tau protein pathology and affect tau aggregation by regulating intracellular and extracellular concentrations of different forms of tau to influence tau-associated neurodegeneration.

    “In microglia, nucleotide-binding oligomerisation domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammatory vesicles have been shown to actively regulate tau protein pathology and affect tau protein aggregation by regulating the intracellular and extracellular concentrations of different forms of tau protein to influence tau-protein-associated neurodegeneration [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Stancu, 2022, The NLRP3 inflammasome modulates tau pathology and neurodegeneration in a tauopathy model, Glia source

      Not checked in the free run.

  • Premisecitation

    Hyperphosphorylation of tau protein and sustained hyperactivation of mTOR signalling in hyperglycaemia may be associated with inhibition of caveolin-1.

    “the hyperphosphorylation of tau protein and sustained hyperactivation of mTOR signalling in hyperglycaemia may be associated with the inhibition of caveolin-1 (Cav-1) [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Wu, 2017, High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction, Oncotarget source

      Not checked in the free run.

  • May combine two claims. 63
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingnone given

    No tau protein-targeted drug has been approved for the market, but some progress has been made in related clinical trials.

    “Although no tau protein-targeted drug has been approved for the market, some progress has been made in related clinical trials (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    These drugs are still in the research and development stage and have not yet been approved for clinical use.

    “However, these drugs are still in the research and development stage and have not yet been approved for clinical use.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the healthy normal adult brain, all six tau isoforms are present with approximately equimolar 4R and 3R isoforms, whereas in the human foetal brain only 0N3R tau is expressed.

    “In the healthy normal adult brain, all six isoforms are present with approximately equimolar 4R and 3R isoforms, whereas in the human foetal brain, only 0N3R tau is expressed [4,5,6,7].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Mandelkow, 2012, Biochemistry and cell biology of tau protein in neurofibrillary degeneration, Cold Spring Harb. Perspect. Med. source

      Not checked in the free run.

    • cites [5] Gorath, 2001, Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes, Glia source

      Not checked in the free run.

    • cites [6] Morris, 2011, The many faces of tau, Neuron source

      Not checked in the free run.

    • cites [7] Waheed, 2023, The Role of Tau Proteoforms in Health and Disease, Mol. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting neuronal structure and function and leading to neuronal death, which triggers the initiation and progression of neurological disorders.

    “Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Tau aggregation in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau aggregation and neurofibrillary tangle formation.

    “The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pathological tau induces synaptic dysfunction by reducing the mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing dendritic spine maturation, disrupting mitochondrial transport and function in synapses, and promoting microglial phagocytosis of synapses.

    “The pathological tau induces synaptic dysfunction in several ways, including reducing the mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia [24,25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Tracy, 2022, Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration, Cell source

      Not checked in the free run.

    • cites [25] Wu, 2021, The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases, Transl. Neurodegener. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Abnormal aggregation and accumulation of tau protein is a pathological feature of a variety of neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, and Parkinson's disease.

    “The abnormal aggregation and accumulation of tau protein is a pathological feature of a variety of neurodegenerative diseases, such as AD, frontotemporal dementia (FTD), and Parkinson’s disease (PD).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pathological tau protein is in a highly phosphorylated state and is cleaved abnormally, resulting in an abnormal conformation and aggregation, which leads to neurofibrillary tauopathies.

    “Pathological tau protein is in a highly phosphorylated state and is cleaved abnormally, resulting in an abnormal conformation and aggregation, which leads to neurofibrillary tauopathies [18,19,20].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Hanger, 2009, Tau phosphorylation: The therapeutic challenge for neurodegenerative disease, Trends Mol. Med. source

      Not checked in the free run.

    • cites [19] Kellogg, 2018, Near-atomic model of microtubule-tau interactions, Science source

      Not checked in the free run.

    • cites [20] Naseri, 2019, The complexity of tau in Alzheimer’s disease, Neurosci. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau binds to axonal microtubules and participates in the stabilisation of microtubules and axonal transport.

    “Tau, a protein that has long been considered to be associated with the axon, binds to axonal microtubules and participates in the stabilisation of microtubules and axonal transport [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Drubin, 1986, Tau protein function in living cells, J. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different conformations of tau protein in the human body can cause tau protein lesions with different symptoms, and these different conformations resemble prion strains.

    “Different conformations of tau protein in the human body can cause tau protein lesions with different symptoms, and these different conformations resemble “prion strains”.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Alonso, 2016, Molecular mechanism of prion-like tau-induced neurodegeneration, Alzheimer’s Dement. J. Alzheimer’s Assoc. source

      Not checked in the free run.

    • cites [22] Colin, 2020, From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy, Acta Neuropathol. source

      Not checked in the free run.

    • cites [23] Glynn, C., Rodriguez, J.A., and Hyman, B.T. (2024). The structural line between prion and “prion-like”: Insights from prion protein and tau. Curr. Opin. Neurobiol., 86. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Hyperphosphorylation of tau leads to its detachment from microtubules, and conformational changes lead to the formation of abnormal paired helices and straight filaments of tau, followed by tau aggregate formation.

    “The hyperphosphorylation of tau protein leads to its detachment from microtubules, and conformational changes lead to the formation of abnormal paired helices and straight filaments of tau protein, followed by the formation of tau protein aggregates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tau protein is a microtubule-associated protein widely distributed in the central nervous system and maintains and regulates neuronal morphology and function.

    “Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Goedert, 1989, Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    White matter lesions are associated with and coexist with hyperphosphorylation of tau protein in the cerebrospinal fluid of patients with Alzheimer's disease.

    “WMLs are associated with and coexist with the hyperphosphorylation of tau protein in the CSF of patients with AD [43,44].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Alexander, 1995, Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: A new perspective, Hypertension source

      Not checked in the free run.

    • cites [44] Shih, 2018, Hypertension Accelerates Alzheimer’s Disease-Related Pathologies in Pigs and 3xTg Mice, Front. Aging Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetylation at Lys274, Lys280, Lys281, and Lys369 impairs tau function and is increased in Alzheimer's disease brains.

    “In addition, acetylation at the Lys274, Lys280, Lys281, and Lys369 sites was shown to impair tau function and to be increased in AD brains [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Tracy, 2016, Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Tau proteins are involved in insulin signalling, and insulin resistance induces tau hyperphosphorylation and lesion formation.

    “Tau proteins are involved in insulin signalling, and insulin resistance also induces tau hyperphosphorylation and lesion formation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    β-amyloid induces hyperphosphorylation of tau in neurons and causes neurofibrillary deposition.

    “β-amyloid induces the hyperphosphorylation of tau in neurons and causes neurofibrillary deposition [34]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Jin, 2011, Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSP and CBD are characterised by inclusion bodies containing 4R tau protein, with clustered astrocyte and oligodendrocyte tangles in PSP and astrocyte plaques in CBD.

    “PSP and CBD are characterised by inclusion bodies containing 4R tau protein, with clustered astrocyte and oligodendrocyte tangles in PSP and astrocyte plaques in CBD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Kovacs, 2019, Molecular pathology of neurodegenerative diseases: Principles and practice, J. Clin. Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The two main pathological features of Alzheimer's disease are extracellular β-amyloid deposition and intracellular hyperphosphorylation of tau protein leading to aggregates and neurofibrillary tangles.

    “The two main pathological features of AD are extracellular β-amyloid (Aβ) deposition and intracellular hyperphosphorylation of tau protein, leading to the formation of aggregates and neurofibrillary tangles (NFTs).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Aberrant N-linked glycosylation of tau may have potential as a biomarker of early Alzheimer's disease and as a marker of Alzheimer's disease progression.

    “This aberrant N-linked glycosylation may have potential as a biomarker of early AD as well as a marker of AD progression [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Haukedal, 2020, Implications of Glycosylation in Alzheimer’s Disease, Front. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PiD is characterised by filamentous 3R tau protein, known as Pick bodies, in neurons, occasional tau-positive branching astrocytes, and rare globular inclusion bodies in oligodendrocytes.

    “PiD is characterised by filamentous 3R tau protein, known as Pick bodies, in neurons, occasional tau-positive branching astrocytes, and rare globular inclusion bodies in oligodendrocytes [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Kovacs, 2019, Molecular pathology of neurodegenerative diseases: Principles and practice, J. Clin. Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of neurofibrillary tangles is positively correlated with the degree of dementia in Alzheimer's disease, and the paired helical filaments that are the major component of neurofibrillary tangles are formed by hyperphosphorylated tau protein.

    “The number of NFTs is positively correlated with the degree of dementia in AD, and the paired helical filaments that are the major component of NFTs are formed by hyperphosphorylated tau protein [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Dermaut, 2005, Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum, Trends Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of tau protein with acetylation at Lys163, Lys174, and Lys180, which inhibits degradation of hyperphosphorylated tau and contributes to accumulation of phosphorylated tau, are detected in brains of patients with mild to moderate Alzheimer's disease.

    “High levels of tau protein with acetylation at the Lys163, Lys174, and Lys180 sites, which inhibits the degradation of hyperphosphorylated tau protein and thus contributes to the accumulation of phosphorylated tau protein, are detected in the brains of patients with mild to moderate AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Tracy, 2016, Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autopsies of Parkinson's disease patients revealed that tau and α-synuclein coexist in Lewy bodies and that tau-α-synuclein interactions influence α-synuclein pathology in Parkinson's disease.

    “Autopsies of PD patients revealed that tau and α-Syn coexist in LBs and that tau-α-Syn interactions influence α-Syn pathology in PD [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Pan, 2021, Tau in the Pathophysiology of Parkinson’s Disease, J. Mol. Neurosci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Huntington's disease is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminal region of Huntington's protein.

    “HD is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminal region of Huntington’s protein (Htt).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In neurodegenerative diseases, aberrant post-translational modifications of tau result in loss of normal regulatory functions, negatively impact normal neuronal functioning, and contribute to the onset and progression of neurological disorders.

    “In neurodegenerative diseases, aberrant post-translational modifications of tau protein result in the loss of normal regulatory functions, which negatively impact the normal functioning of neurons and contribute to the onset and progression of neurological disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Huntington's disease patients and the R6/2 mouse model, phosphorylation of tyrosine 216 is increased, expression of CaMKII, ERK1/2, and CDK5 is downregulated, and GSK-3β activity is reduced.

    “In HD patients and the R6/2 mouse model, the phosphorylation level of tyrosine 216 is increased; the expression of CaMKII, ERK1/2, and CDK5 is downregulated; and the activity of GSK-3β is reduced [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Mees, 2023, Implications of Tau Dysregulation in Huntington’s Disease and Potential for New Therapeutics, J. Huntington’s Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Parkinson's disease pathology is characterised by progressive loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies.

    “PD is the second most common neurodegenerative disease, and the pathology of PD is characterised by the progressive loss of nigrostriatal dopaminergic neurons and the formation of neuronal Lewy bodies (LBs).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reduced expression of calmodulin neurophosphatase has been observed in Huntington's disease patients, and mutant Huntington's protein can induce aberrant tau hyperphosphorylation in vivo via dysregulation of calmodulin neurophosphatase.

    “A reduced expression of calmodulin neurophosphatase has been observed in HD patients, and mutant Htt proteins can induce aberrant tau protein hyperphosphorylation in vivo via the dysregulation of calmodulin neurophosphatase [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Gratuze, 2015, Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington’s disease, Hum. Mol. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Post-translational modifications of tau include phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, heterodimerisation, and truncation, and can affect tau structure and function and its localisation and regulation in neuronal axons.

    “These post-translational modifications include phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, heterodimerisation, and truncation [53,54] and can affect the structure and function of tau protein and thus its localisation and regulation in neuronal axons.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Hernandez, 2007, Tauopathies, Cell Mol. Life Sci. source

      Not checked in the free run.

    • cites [54] Kaur, 2023, Role of Tau in Various Tauopathies, Treatment Approaches, and Emerging Role of Nanotechnology in Neurodegenerative Disorders, Mol. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau-modified α-synuclein protofibrils have stronger spreading activity than pure α-synuclein protofibrils and induce mitochondrial dysfunction, synaptic dysfunction, and neurotoxicity.

    “that tau-modified α-Syn protofibrils have a stronger spreading activity than pure α-Syn protofibrils and induce mitochondrial dysfunction, synaptic dysfunction, and neurotoxicity;”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Pan, 2022, Tau accelerates alpha-synuclein aggregation and spreading in Parkinson’s disease, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding of tau and α-synuclein leads to an increase in abundance of insoluble, high-molecular-weight α-synuclein and co-localisation of aggregates of tau and α-synuclein.

    “This binding leads to an increase in the abundance of insoluble, high-molecular-weight α-syn and the co-localisation of aggregates of tau and α-syn.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Jensen, 1999, α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau proteins interact with α-synuclein and accelerate its aggregation.

    “Lina Pan et al. demonstrated that tau proteins interact with α-Syn and accelerate its aggregation;”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Pan, 2022, Tau accelerates alpha-synuclein aggregation and spreading in Parkinson’s disease, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Mutant Huntington's protein and tau protein deposits occur in the same neuronal subpopulation, but the two proteins do not interact.

    “Mutant Htt and tau protein deposits occur in the same neuronal subpopulation, but the two proteins do not interact.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    White matter lesion is an important risk factor for postoperative cognitive dysfunction in humans, and tau protein hyperphosphorylation can be induced by surgery performed under general anaesthesia.

    “Interestingly, WML is an important risk factor for POCD in humans, and tau protein hyperphosphorylation can be induced by surgery performed under general anaesthesia [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Nakao, 2019, Brain white matter lesions and postoperative cognitive dysfunction: A review, J. Anesth. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reported tau protein alterations in Huntington's disease include an increase in total levels, an imbalance of isoforms produced by selective splicing with an increased 4R-/3R-tau ratio, and post-translational modifications such as hyperphosphorylation or truncation.

    “The reported tau protein alterations include an increase in total levels, an imbalance of isoforms produced by selective splicing (an increased 4R-/3R-tau ratio), and post-translational modifications (e.g., hyperphosphorylation or truncation) [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Lucas, 2020, Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease, Front. Cell. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau and α-synuclein are colocalised in cellular axons, and in neuronal cells they interact directly via binding sites in the C-terminal region of α-synuclein (55-140 aa) and the microtubule-binding region of tau (192-383 aa).

    “Tau and α-syn are colocalised in cellular axons, and in neuronal cells, they interact directly via binding sites in the c-terminal region of α-syn (55–140 aa) and the microtubule-binding region of tau (192–383 aa);”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Jensen, 1999, α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356, J. Biol. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Racial and ethnic variations exist in the magnitude of association between the ApoEε4 allele and risk of developing Alzheimer's disease and related dementias.

    “Emerging research has shown racial and ethnic variations in the magnitude of association between the apolipoprotein ApoEε4 allele and the risk of developing Alzheimer’s disease and related dementias (ADRDs).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Wang, 2021, The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers, J. Alzheimers Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The frequency of ApoEε4 carriers is highest among the African American population, followed by the African population, the white population, the Hispanic/Latino population, and the Chinese population.

    “The frequency of ApoEε4 carriers was found to be highest among the African American population, followed by the African population, the white population, the Hispanic/Latino population, and the Chinese population [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Wang, 2021, The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers, J. Alzheimers Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Propofol-mediated cognitive dysfunction in rats may be related to hyperphosphorylation of tau protein, leading to re-entry of neuronal cells into the cell cycle, resulting in apoptosis.

    “Propofol-mediated cognitive dysfunction in rats may be related to the hyperphosphorylation of tau protein, leading to the re-entry of neuronal cells into the cell cycle, which results in apoptosis [151].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Zheng, 2018, Hyperphosphorylation of protein Tau in hippocampus may cause cognitive dysfunction of propofol-anesthetized rats, Eur. Rev. Med. Pharmacol. Sci.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Exposure to air pollutants, pesticides, metal-containing nanoparticles, and metalloids such as arsenic, mercury, lead, and cadmium may increase the risk of tau protein hyperphosphorylation.

    “Exposure to several environmental factors, such as air pollutants, pesticides, metal-containing nanoparticles, and many metalloids, such as arsenic, mercury, lead, and cadmium, may increase the risk of tau protein hyperphosphorylation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In AD, intracerebral iron overload is a key pathological feature that occurs in conjunction with tau hyperphosphorylation.

    “In AD, intracerebral iron overload is a key pathological feature that occurs in conjunction with tau hyperphosphorylation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Wan, 2019, Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling, Front. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperphosphorylation of tau and disruption of insulin signalling in the brain were induced in iron-overloaded mice.

    “The hyperphosphorylation of tau and disruption of insulin signalling in the brain were reported to be induced in iron-overloaded mice [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Wan, 2019, Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling, Front. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferrous chloride leads to aberrant phosphorylation of tau and decreases tyrosine phosphorylation levels of IRβ and IRS-1 via the PI3K p85a subunit.

    “Ferrous chloride (Fe2+) leads to the aberrant phosphorylation of tau and decreases tyrosine phosphorylation levels of insulin receptor β (IRβ) and insulin signalling substrate 1 (IRS-1) via the phosphatidylinositol PI3K kinase p85a subunit.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Wan, 2019, Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling, Front. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anaesthetic drugs such as propofol and sevoflurane can cause abnormal phosphorylation of tau protein in the hippocampus and are closely associated with degenerative changes in the central nervous system.

    “Anaesthetic drugs such as propofol and sevoflurane can cause an abnormal phosphorylation of tau protein in the hippocampus and are closely associated with degenerative changes in the central nervous system.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [151] Zheng, 2018, Hyperphosphorylation of protein Tau in hippocampus may cause cognitive dysfunction of propofol-anesthetized rats, Eur. Rev. Med. Pharmacol. Sci.

      Not checked in the free run.

    • cites [152] Brouillette, 2012, Tau phosphorylation and sevoflurane anesthesia: An association to postoperative cognitive impairment, Anesthesiology source

      Not checked in the free run.

    • cites [153] Yu, 2020, Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Epidemiological and experimental studies have demonstrated that exposure to heavy-metal pollutants has a long-term effect on the central nervous system, potentially through epigenetic modifications, which can stimulate the development of neurodevelopmental disorders and neurodegenerative diseases.

    “Epidemiological and experimental studies have demonstrated that exposure to heavy-metal pollutants has a long-term effect on the central nervous system (CNS), potentially through epigenetic modifications, which can stimulate the development of neurodevelopmental disorders and neurodegenerative diseases [148,149,150].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [148] Mateo, 2023, Metals linked with the most prevalent primary neurodegenerative dementias in the elderly: A narrative review, Environ. Res. source

      Not checked in the free run.

    • cites [149] Newell, 2024, Prevalence rates of neurodegenerative diseases versus human exposures to heavy metals across the United States, Sci. Total Environ. source

      Not checked in the free run.

    • cites [150] Yu, 2024, Neurotoxic effects of heavy metal pollutants in the environment: Focusing on epigenetic mechanisms, Environ. Pollut. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Okadaic acid is a potent and selective inhibitor of PP1 and PP2A protein phosphatases and has proven to be a potent tool for study of regulatory mechanisms and neurotoxicity associated with tau hyperphosphorylation.

    “Okadaic acid (OKA), a polyether C38 fatty acid toxin derived from the black sponge Hallichondria okadaii, is a potent and selective inhibitor of the PP1 and PP2A protein phosphatases, and OKA has proven to be a potent tool for the study of various regulatory mechanisms and neurotoxicity associated with the hyperphosphorylation of tau protein [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Kamat, 2014, Molecular and cellular mechanism of okadaic acid (OKA)-induced neurotoxicity: A novel tool for Alzheimer’s disease therapeutic application, Mol. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Isorhynchophylline improves cognitive function by reducing Aβ production and deposition, tau protein hyperphosphorylation, and neuroinflammation and has potential as a pharmacological treatment aiming to prevent further progression to AD.

    “By inhibiting activation of the JNK signalling pathway, isorhynchophylline (IRN) improves cognitive function by reducing Aβ production and deposition, tau protein hyperphosphorylation, and neuroinflammation and has potential as a pharmacological treatment aiming to prevent further progression to AD [188].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Li, 2019, Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: Studies in a transgenic mouse model of Alzheimer’s disease, Brain Behav. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Saracatinib reduces tau aggregation, increases synaptic density, and improves memory.

    “Saracatinib is a small-molecule inhibitor of Fyn kinase that reduces tau aggregation, increases synaptic density, and improves memory [177,178,179,180].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [177] Nygaard, 2014, Fyn kinase inhibition as a novel therapy for Alzheimer’s disease, Alzheimer’s Res. Ther. source

      Not checked in the free run.

    • cites [178] Nygaard, 2018, Targeting Fyn Kinase in Alzheimer’s Disease, Biol. Psychiatry source

      Not checked in the free run.

    • cites [179] Tang, 2020, Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy, Acta Neuropathol. Commun. source

      Not checked in the free run.

    • cites [180] Wadhwa, 2020, Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors, Curr. Top. Med. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sevoflurane treatment induces neuroinflammation by upregulating expression of full-length ApoE and ApoE-containing 18 kDa fragments in naive hippocampal neurons and by increasing tau protein phosphorylation.

    “Sevoflurane treatment induces neuroinflammation by upregulating the expression of full-length ApoE and ApoE-containing 18 kDa fragments in naive hippocampal neurons and by increasing tau protein phosphorylation [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Yu, 2020, Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tideglusib failed to improve cognition in a phase 2 clinical study, and CSF levels of Aβ42, total tau, and pTau181 were not altered.

    “Tideglusib, a small-molecule GSK3β inhibitor, failed to improve cognition in a phase 2 clinical study, and CSF levels of Aβ42, total tau, and pTau181 were not altered, resulting in failure of the trial [175,176].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [175] Hoglinger, 2014, Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial, Mov. Disord. source

      Not checked in the free run.

    • cites [176] Lovestone, 2015, A phase II trial of tideglusib in Alzheimer’s disease, J. Alzheimers Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lithium salts failed to demonstrate neuroprotective activity or improvements in cognitive or psychometric scores and did not affect CSF Aβ42, pTau181, pTau231, or total tau levels.

    “lithium salts failed to demonstrate neuroprotective activity or improvements in cognitive or psychometric scores and did not affect CSF Aβ42, pTau181, pTau231, or total tau levels [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Wiseman, 2023, Lithium Provides Broad Therapeutic Benefits in an Alzheimer’s Disease Mouse Model, J. Alzheimers Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CIG inhibits GSK-3β activity to enhance PP2A activity via suppression of PME-1-induced demethylation of PP2Ac, thereby modulating crosstalk between GSK-3β and PP2A signalling pathways and inhibiting hyperphosphorylation of tau protein.

    “In addition, CIG inhibited GSK-3β activity to enhance PP2A activity via suppression of the PME-1-induced demethylation of PP2Ac, thereby modulating the crosstalk between the GSK-3β and PP2A signalling pathways and thus inhibiting the hyperphosphorylation of tau protein.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Yang, 2018, Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3beta and PP2A Signaling, Front. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nilotinib had some effect on CSF and frontal cortex amyloid levels in a phase 2 clinical trial but failed to exert an effect on tau.

    “Nilotinib, a small-molecule inhibitor of Bcr-Abl, had some effect on CSF and frontal cortex amyloid levels in a phase 2 clinical trial but failed to exert an effect on tau [181,182,183].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [181] Pagan, 2020, Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial, JAMA Neurol. source

      Not checked in the free run.

    • cites [182] Turner, 2020, Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer’s Disease, Ann. Neurol. source

      Not checked in the free run.

    • cites [183] Stevenson, 2023, Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer’s disease, J. Neuroinflammation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exosomes carrying curcumin enable curcumin to cross the blood-brain barrier and inhibit phosphorylation of tau protein by activating the AKT/GSK-3β pathway, better preventing neuronal death in vivo and in vitro and alleviating AD symptoms.

    “Hao Wang’s team designed exosomes carrying curcumin (cur) to enable curcumin to cross the blood-brain barrier (BBB) and inhibit the phosphorylation of tau protein by activating the AKT/GSK-3β pathway, better preventing neuronal death in vivo and in vitro and alleviating AD symptoms [187].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Wang, 2019, Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3beta pathway, Nanoscale source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Anti-tau protein monoclonal antibodies are a promising therapeutic strategy, but further exploration of their mechanism of action and side-effects is still needed.

    “anti-tau protein monoclonal antibodies are a promising therapeutic strategy, but further exploration of their mechanism of action and side-effects is still needed [194].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Yanamandra, 2017, Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy, Sci. Transl. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Some antiviral drugs such as lamivudine and acyclovir have been shown to inhibit aberrant aggregation of tau protein.

    “Some antiviral drugs, such as lamivudine and acyclovir, have also been shown to inhibit the aberrant aggregation of tau protein”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Curcumin reduces tau and Aβ pathology and ameliorates cognitive deficits.

    “it has been demonstrated to reduce tau and Aβ pathology and ameliorate cognitive deficits.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [192] Hamaguchi, 2010, REVIEW: Curcumin and Alzheimer’s disease, CNS Neurosci. Ther. source

      Not checked in the free run.

    • cites [193] Li, 2023, Research Mechanism and Progress of the Natural Compound Curcumin in Treating Alzheimer’s Disease, Mini Rev. Med. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Y01 specifically targets tau-acK280 and, upon interaction with acetylated tau protein aggregates, prevented progression of tauopathy and increased neuronal viability.

    “The researchers developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of the Y01-acK280 peptide complex; upon interaction with acetylated tau protein aggregates, Y01 prevented the progression of tauopathy and increased neuronal viability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Song, 2023, Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280–acetylated tau in cell and mouse models, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LMTX (TRx0237) is a small-molecule tau protein aggregation inhibitor that prevents tau protein aggregation or degrades preexisting aggregates.

    “The methylene blue derivative LMTX (TRx0237) is a small-molecule tau protein aggregation inhibitor that prevents tau protein aggregation or degrades preexisting aggregates [190].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Wang, 2021, Small molecule therapeutics for tauopathy in Alzheimer’s disease: Walking on the path of most resistance, Eur. J. Med. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vallitinib inhibits EGFR/HER-2 via DYRK1A and ameliorates the early stages of neuroinflammatory responses and tau protein pathology.

    “Vallitinib inhibits EGFR/HER-2 via DYRK1A and ameliorates the early stages of neuroinflammatory responses and tau protein pathology [203].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Kim, 2022, Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A, Front. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AADvac1 significantly slowed growth of NFTs in the blood, with significant reduction in CSF pTau217 levels and a trend towards reduction in pTau181 and total tau levels in the treatment group, but no cognitive benefit was observed.

    “AADvac1 significantly slowed the growth of NFTs in the blood, with a significant reduction in CSF pTau217 levels and a trend towards a reduction in pTau181 and total tau levels in the treatment group, but no cognitive benefit was observed [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Vaz, 2020, Alzheimer’s disease: Recent treatment strategies, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A bispecific nanobody targeting a blood-brain barrier receptor and a tau capping inhibitor can improve blood-brain barrier penetration and blocked seeding by recombinant tau oligomers.

    “Romany Abskharon’s team designed a bispecific nanobody, consisting of a nanobody targeting a receptor on the BBB and a nanobody tau capping inhibitor linked by a flexible linker, that can improve blood–brain barrier penetration and blocked seeding by recombinant tau oligomers [198].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] Abskharon, 2023, Structure-based design of nanobodies that inhibit seeding of Alzheimer’s patient-extracted tau fibrils, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Focused ultrasound applied together with microbubbles (FUS + MB) is a novel technique to transiently open the blood-brain barrier and enhance drug delivery, developing ultrasound-mediated delivery of aducanumab and anti-Tau antibodies.

    “Focused ultrasound applied together with microbubbles (FUS + MB) is a novel technique to transiently open the BBB and enhance drug delivery, developing the ultrasound-mediated delivery of aducanumab and anti-Tau antibodies [199].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Wasielewska, 2022, A sporadic Alzheimer’s blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies, Theranostics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Curcumin reduces tau lesions in animal models and prevents tau accumulation in vitro.

    “Curcumin reduces tau lesions in animal models and prevents tau accumulation in vitro.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [192] Hamaguchi, 2010, REVIEW: Curcumin and Alzheimer’s disease, CNS Neurosci. Ther. source

      Not checked in the free run.

    • cites [193] Li, 2023, Research Mechanism and Progress of the Natural Compound Curcumin in Treating Alzheimer’s Disease, Mini Rev. Med. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methylation of tau protein is a contributing factor in tau pathogenesis and may be a potential therapeutic drug target for different tauopathies.

    “The methylation of tau protein is a contributing factor in tau pathogenesis and may be a potential therapeutic drug target for the treatment of different tauopathies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Xia, Y., Bell, B.M., and Giasson, B.I. (2023). Tau Lysine Pseudomethylation Regulates Microtubule Binding and Enhances Prion-like Tau Aggregation. Int. J. Mol. Sci., 24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LMTX has failed to achieve positive results in three completed clinical studies, and one phase 1/3 clinical study is underway.

    “The drug has failed to achieve positive results in the three clinical studies that have been completed to date, and there is still one phase 1/3 clinical study underway [191].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] Harrington, 2015, Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease, J. Biol. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Abnormal aggregation of tau protein and neuronal damage are key processes in the onset and progression of neurodegenerative diseases.

    “The abnormal aggregation of tau protein and neuronal damage are key processes in the onset and progression of neurodegenerative diseases”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Treatment during the therapeutic window is of great importance for the effectiveness of tau protein-targeted therapy.

    “treatment during the therapeutic window is of great importance for the effectiveness of tau protein-targeted therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Treatments for tau protein-related diseases mainly involve inhibition of abnormal tau protein aggregation and degradation of tau protein aggregates.

    “The treatments for tau protein-related diseases mainly involve the inhibition of abnormal tau protein aggregation and the degradation of tau protein aggregates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Tau protein is an important pathological feature in neurodegenerative diseases.

    “Tau protein is an important pathological feature in neurodegenerative diseases”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Various neurodegenerative diseases can lead to abnormal aggregation of tau protein and neuronal damage due to different genetic and environmental factors.

    “various neurodegenerative diseases can lead to the abnormal aggregation of tau protein and neuronal damage due to different genetic and environmental factors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Tau protein is a highly complex protein with different splicing isoforms and post-translational modifications that can affect its structure and function.

    “which is a highly complex protein with different splicing isoforms and post-translational modifications that can affect the structure and function of the tau protein.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Several studies have demonstrated the effectiveness of therapeutic strategies such as anti-tau protein immunotherapy, pharmacological interventions, and gene therapy.

    “Several studies have demonstrated the effectiveness of therapeutic strategies such as anti-tau protein immunotherapy, pharmacological interventions, and gene therapy”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Researchers successfully achieved dephosphorylation of tau protein with PhosTAC and confirmed that this approach can reduce pathogenic pathological properties of tau protein.

    “The researchers successfully achieved the dephosphorylation of tau protein with PhosTAC and confirmed that this approach can reduce the pathogenic pathological properties of tau protein”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [205] Chen, 2021, Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs), ACS Chem. Biol. source

      Not checked in the free run.

    • cites [206] Hu, 2023, Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality, J. Am. Chem. Soc. source

      Not checked in the free run.

    • cites [207] Hu, Z., and Crews, C.M. (2022). Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic. Chembiochem A Eur. J. Chem. Biol., 23. source

      Not checked in the free run.

74 of 74

  • The paper relies on this without support.

    Tau protein abundance in cerebrospinal fluid increases more than 30 years before the onset of Alzheimer’s disease.

    “Tau protein, whose abundance in the cerebrospinal fluid (CSF) increases more than 30 years before the onset of AD, is an integral part of the pathogenesis of AD.”

  • The paper relies on this without support.

    Tau protein is an integral part of the pathogenesis of Alzheimer’s disease.

    “Tau protein, whose abundance in the cerebrospinal fluid (CSF) increases more than 30 years before the onset of AD, is an integral part of the pathogenesis of AD.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The goal of tau treatments is to prevent tau from aggregating and spreading.

    “The goal of tau treatments is to prevent tau from aggregating and spreading.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [200]

  • The accumulation of tau protein in neurofibrillary tangles, known as tau protein modulation, provides a novel venue for disease modification.

    “The accumulation of tau protein in neurofibrillary tangles, which is known as tau protein modulation, provides a novel venue for disease modification.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [200]

  • Numerous approaches, such as tau aggregation inhibitors, are being studied to address the tau protein problem and prevent tau tangle formation.

    “Numerous approaches, such as tau aggregation inhibitors, are being studied in an effort to address the tau protein problem and prevent tau tangle formation.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [200]

  • There is evidence that tau vaccinations may slow the disease's course by reducing tau protein accumulation.

    “First, there is evidence that tau vaccinations may slow the disease’s course by reducing tau protein accumulation [198,199,200,201].”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [200]

  • Techniques for tau immunotherapy, such as those being tried with AADvac1, function by teaching the immune system to eliminate aberrant tau proteins from the brain.

    “Techniques for tau immunotherapy, such as those being tried with AADvac1, function by teaching the immune system to eliminate aberrant tau proteins from the brain.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [200]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposing effects of GSK-3β on PP2A activity

    Minor

    The paper says GSK-3β inhibits PP2A, but also says that upregulating GSK-3β increases PP2A activity. It does not distinguish the conditions under which these opposite effects occur.

  • Periodontal pathogen has different genus in text and cited reference

    Minor

    The text names the organism as Clostridium nucleatum, whereas the cited study's title names it Fusobacterium nucleatum.

2 of 2

Cites

Flagged first, then by citations

5 of the 207 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Alzforum (2024, May 22). Antisense Therapy Stifles CSF Tau in Mild Alzheimer’s Disease. Available online: https://www.alzforum.org/news/conference-coverage/antisense-therapy-stifles-csftau-mild-alzheimers-disease-0.
  2. (2024, May 22). Eisai. Eisai Presents Data Showing Quantification of Tau Microtubule Binding Region in Cerebrospinal Fluid and the Identification of a Target Engagement Biomarker for the New Anti-Tau Antibody E2814 at Alzheimer’s Association International Conference (AAIC). Available online: https://www.eisai.com/news/2019/news201955.html.

Cited by

Sorted by citations

Related

Authors
Yang, J., Zhi, W., & Wang, L.
Affiliations
  • Academy of Military Medical Sciences (CN)
  • Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
Corresponding author
  • Zhi, Weijia
  • Wang, Lifeng
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2024-06-13
Volume
29
Issue
12
Pages
2812
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules29122812
PMC
PMC11206543
OpenAlex
W4399611766
Semantic Scholar
cb596fc2001f1e4f1f7b4bc5cc50f3358e089a04
Cited by
63
References
207
Citations by year
2026: 25 · 2025: 30 · 2024: 8
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (62171457, 20BJZ49)
  • Logistics Research Program (62171457, 20BJZ49)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tau protein, neurodegenerative diseases, tau aggregation, neurofibrillary tangles, post-translational modification, microtubule-associated proteins, drug discovery, neuronal cell death
MeSH terms
Drug Development, Animals, Humans, Protein Processing, Post-Translational, Neurofibrillary Tangles, tau Proteins, Neurodegenerative Diseases, Molecular Targeted Therapy, Protein Aggregation, Pathological

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review