CoChat
Sign Up
Cited by 329Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

The DOI matches its Crossref record; 228 of the 228 references it cites were found in a registry or an index.

Tauopathies: new perspectives and challenges

Open access
Zhang, Yi, Wu, Kai-Min, Yang, Liu, Dong, Qiang, Yu, Jin-Tai·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00533-zPMC PMC8991707
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body: Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Conclusions: Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13024-022-00533-z

Cites

228 of 228 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 MAPT pathological mutations in exons, haplotypes, and alternative splicing. MAPT (microtubule associated protein tau) gene, located on chromosome 17q21.3, has been identified with over 100 mutations, and pathological mutations associated with increased risk for tauopathies are shown above. The difference between H1 and H2 haplotypes is a 900 kb inversion existing in the largest linkage disequilibrium (LD) area in chromosome 17. Besides, H1 and its various sub-haplotypes usually contribute to disease occurrence, while H2 haplotype often act as a protective factor. Alternative splicing is common in neuronal cells which help to increase genetic plasticity and the diversity of proteome under physiological conditions [6]. However, imbalance in the ratio of the 3R and 4R isoforms can give rise to the pathogenesis of tauopathies, as the 4R tau is more efficient in promoting microtubule assembly with an extra repeat domain R2 which hyper-stabilize MT and more free-floating tau leads to aggregates formation [3, 6, 7]
Fig. 1 MAPT pathological mutations in exons, haplotypes, and alternative splicing. MAPT (microtubule associated protein tau) gene, located on chromosome 17q21.3, has been identified with over 100 mutations, and pathological mutations associated with increased risk for tauopathies are shown above. The difference between H1 and H2 haplotypes is a 900 kb inversion existing in the largest linkage disequilibrium (LD) area in chromosome 17. Besides, H1 and its various sub-haplotypes usually contribute to disease occurrence, while H2 haplotype often act as a protective factor. Alternative splicing is common in neuronal cells which help to increase genetic plasticity and the diversity of proteome under physiological conditions [6]. However, imbalance in the ratio of the 3R and 4R isoforms can give rise to the pathogenesis of tauopathies, as the 4R tau is more efficient in promoting microtubule assembly with an extra repeat domain R2 which hyper-stabilize MT and more free-floating tau leads to aggregates formation [3, 6, 7]CC BY · PubMed Central
Fig. 2 Spatial–temporal distribution of tau lesions in schemes of brains. Deeper color means earlier involvement. A Tau progression in PiD has four stages, shown in medial and lateral views. Stage I, tau affects angular gyrus, limbic and frontotemporal regions. Stage II/III involves white matter tracts, subcortical structures (thalamus, striatum), serotonergic/noradrenergic brainstem nuclei, primary motor cortex and pre-cerebellar nuclei. Stage IV, tau invades visual cortex and cerebellar. Modified from [84]. B Tau progression in AD has six stages. Stage I/II, tau affect transentorhinal area. Stage III/IV, severe involvement of entorhinal, hippocampus and limbic areas happens. Stage V/VI, tau reaches primary and secondary neocortex. Modified from [85, 86]. C Tau progression in PSP has seven stages. Stage 0/I, pallido-luyso-nigral axis shows tau burden. Stage II/III, tau invades basal ganglia, dentate nucleus and pedunculopontine nucleus. Stage IV/V, tau reaches frontoparietal and temporal lobes. Stage VI/VII, occipital cortices, substantia nigra, subthalamic nucleus and globus pallidus are involved. Modified from [55]. D Tau progression in CTE has four stages, shown in coronal view at levels of genu of corpus callosum, mammillary body, and lateral geniculate body. Stage I/II, tau is restricted focally deep in the sulci of cortex, especially frontal lobe, surrounding small vessels and expand to superficial layers. Stage III, tau is widespread to cortices including frontal, temporal, parietal, and insular lobes. Meanwhile, amygdala, hippocampus, and entorhinal cortex are involved. Stage IV, tau affects most regions of cerebral cortex. Modified from [87]. E Tau progression (argyrophilic grains (AGs)) in AGD has four stages, shown in view same as D. Stage I is characterized by AGs in ambient gyrus, hippocampus (CA1), entorhinal and amygdala. Stage II shows involvement of medial temporal lobe and subiculum. Stage III, AGs reaches anterior temporal, cingulate gyrus, rectus gyrus, septum, accumbens nucleus, insular and orbitofrontal cortices, and hypothalamus (CA2 CA3). Stage IV involves neocortex and brainstem (not shown in figures). Modified from [63]
Fig. 2 Spatial–temporal distribution of tau lesions in schemes of brains. Deeper color means earlier involvement. A Tau progression in PiD has four stages, shown in medial and lateral views. Stage I, tau affects angular gyrus, limbic and frontotemporal regions. Stage II/III involves white matter tracts, subcortical structures (thalamus, striatum), serotonergic/noradrenergic brainstem nuclei, primary motor cortex and pre-cerebellar nuclei. Stage IV, tau invades visual cortex and cerebellar. Modified from [84]. B Tau progression in AD has six stages. Stage I/II, tau affect transentorhinal area. Stage III/IV, severe involvement of entorhinal, hippocampus and limbic areas happens. Stage V/VI, tau reaches primary and secondary neocortex. Modified from [85, 86]. C Tau progression in PSP has seven stages. Stage 0/I, pallido-luyso-nigral axis shows tau burden. Stage II/III, tau invades basal ganglia, dentate nucleus and pedunculopontine nucleus. Stage IV/V, tau reaches frontoparietal and temporal lobes. Stage VI/VII, occipital cortices, substantia nigra, subthalamic nucleus and globus pallidus are involved. Modified from [55]. D Tau progression in CTE has four stages, shown in coronal view at levels of genu of corpus callosum, mammillary body, and lateral geniculate body. Stage I/II, tau is restricted focally deep in the sulci of cortex, especially frontal lobe, surrounding small vessels and expand to superficial layers. Stage III, tau is widespread to cortices including frontal, temporal, parietal, and insular lobes. Meanwhile, amygdala, hippocampus, and entorhinal cortex are involved. Stage IV, tau affects most regions of cerebral cortex. Modified from [87]. E Tau progression (argyrophilic grains (AGs)) in AGD has four stages, shown in view same as D. Stage I is characterized by AGs in ambient gyrus, hippocampus (CA1), entorhinal and amygdala. Stage II shows involvement of medial temporal lobe and subiculum. Stage III, AGs reaches anterior temporal, cingulate gyrus, rectus gyrus, septum, accumbens nucleus, insular and orbitofrontal cortices, and hypothalamus (CA2 CA3). Stage IV involves neocortex and brainstem (not shown in figures). Modified from [63]CC BY · PubMed Central
Fig. 3 Clinicopathological correlations of tauopathies. In the row listing clinical syndromes, combination of colors depicts the pathology composition within one phenotype. In the row listing neuropathology, different colors represent the classification of tauopathies based on tau isoforms primarily exist in aggregates. The solid lines connect pathologies and their frequently associated phenotypes, while dotted lines show infrequent associations. AD Alzheimer’s disease, aAD amnestic AD, PCA posterior cortical atrophy, lvPPA logopenic variant primary progressive aphasia, bvAD behavioral dysexecutive variant AD, CN cognitively normal, RS Richardson syndrome, P parkinsonism, PGF progressive gait freezing, CBS corticobasal syndrome, FTD frontotemporal dementia, bvFTD behaviour variant of frontotemporal dementia, nfvPPA non-fluent/agrammatic variant of primary progressive aphasia, svPPA Semantic variant of primary progressive aphasia, CTE chronic traumatic encephalopathy, PART primary age-related tauopathy, PiD Pick’s disease, AGD argyrophilic grain disease, CBD corticobasal degeneration, PSP progressive supranuclear palsy, GGT globular glial tauopathy
Fig. 3 Clinicopathological correlations of tauopathies. In the row listing clinical syndromes, combination of colors depicts the pathology composition within one phenotype. In the row listing neuropathology, different colors represent the classification of tauopathies based on tau isoforms primarily exist in aggregates. The solid lines connect pathologies and their frequently associated phenotypes, while dotted lines show infrequent associations. AD Alzheimer’s disease, aAD amnestic AD, PCA posterior cortical atrophy, lvPPA logopenic variant primary progressive aphasia, bvAD behavioral dysexecutive variant AD, CN cognitively normal, RS Richardson syndrome, P parkinsonism, PGF progressive gait freezing, CBS corticobasal syndrome, FTD frontotemporal dementia, bvFTD behaviour variant of frontotemporal dementia, nfvPPA non-fluent/agrammatic variant of primary progressive aphasia, svPPA Semantic variant of primary progressive aphasia, CTE chronic traumatic encephalopathy, PART primary age-related tauopathy, PiD Pick’s disease, AGD argyrophilic grain disease, CBD corticobasal degeneration, PSP progressive supranuclear palsy, GGT globular glial tauopathyCC BY · PubMed Central
Fig. 4 Tau related therapies. Considering the pathogenic pathways existing in tauopathies, potential therapeutic methods include MAPT expression suppression, alternative splicing regulation, microtubule stabilization, post-translational modification adjustment, aggregation inhibition, tau clearance activation, and passive or active immunization. PPA phosphatase activator, P phosphate, Ac acetyl group, Gly O-linked N-acetylglucosamine (Gly) residues, PHF paired helical filament, NFTs neurofibrillary tangles, Ub ubiquitination; Created with BioRender.com.
Fig. 4 Tau related therapies. Considering the pathogenic pathways existing in tauopathies, potential therapeutic methods include MAPT expression suppression, alternative splicing regulation, microtubule stabilization, post-translational modification adjustment, aggregation inhibition, tau clearance activation, and passive or active immunization. PPA phosphatase activator, P phosphate, Ac acetyl group, Gly O-linked N-acetylglucosamine (Gly) residues, PHF paired helical filament, NFTs neurofibrillary tangles, Ub ubiquitination; Created with BioRender.com.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

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

The self-check needs the paper’s full text.

Citations

Cites

1 retracted

Show all 228 references

Research works printed but not linked: 1

  1. Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Höglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017. https://doi.org/10.1016/s1474-4422(17)30157-6. · DOI · Paper page

Cited by

Sorted by citations

Items 201–300 of 329

Related

See all

Metadata

Authors
Zhang, Y., Wu, K.-M., Yang, L., Dong, Q., & Yu, J.-T.
Affiliations
Shanghai Medical College of Fudan University (CN)
Corresponding author
Yu, Jin-Tai
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-04-07
Volume
17
Issue
1
Pages
28-28
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00533-z
PMC
PMC8991707
OpenAlex
W4223629343
Cited by
323
References
228
Citations by year
2026: 69 · 2025: 83 · 2024: 97 · 2023: 60 · 2022: 14
FWCI
8.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (91849126)
  • Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
tauopathy, tau protein, neurodegenerative diseases, tau isoforms, tau biomarkers, cerebrospinal fluid biomarkers, blood-based biomarkers, neuroimaging, disease-modifying therapy, early diagnosis
MeSH terms
Inclusion Bodies, Humans, Neurons, tau Proteins, Neurodegenerative Diseases, Protein Isoforms, Tauopathies

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.

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