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Cells
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Recent Advances in the Study of Tau Protein
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Recent Advances in the Study of Tau Protein

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Neuroscience".

Deadline for manuscript submissions: 20 May 2026 | Viewed by 8271

Special Issue Editor

Dr. Santosh Jadhav

E-Mail Website
Guest Editor
Department of Glycoconjugates, Institute of Chemistry, Slovak Academy of Sciences, Dubravska 9, 845 36 Bratislava, Slovakia
Interests: Alzheimer’s disease; tau; lyve1; macrophages; meninges
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tau, an intrinsically disordered protein first discovered as a component of neurofibrillary tangles in Alzheimer's disease, is also a crucial protein in a group of neurodegenerative disorders known as tauopathies. The protein undergoes a multitude of post-translational and structural changes, which disrupt its function and contribute to these deadly disorders. Throughout the disease, tau changes from an inflexible state to filaments with unique morphologies for the disorders involved. In addition to its cardinal role as a protein capable of polymerizing and stabilizing microtubules, various novel and intriguing functions of tau have been discovered in recent decades, raising the prospect that the protein may have a significant impact on the central nervous system. Furthermore, the mechanisms by which tau can play a role in disease etiology are constantly investigated and unraveled.

In this Special Issue, we invite original research articles (in vitro, animal, and human investigations, as well as in silico studies), review articles, and perspectives that will drive ongoing efforts to better understand tau protein in physiology and disease. We welcome submissions on a wide range of topics, including (but not limited to) tau structure and function, mechanism of action, immunological modulatory variables, aggregation and pathogenesis, interactions with tau binding partners, experimental therapeutics, tauopathy models, and biomarkers.

Dr. Santosh Jadhav
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tau protein
  • post-translational modification
  • tauopathy filaments
  • neuro-immune interactions

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Published Papers (2 papers)

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Review

14 pages, 930 KB  
Review
Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies
by Itzhak Fischer and Peter W. Baas
Cells 2026, 15(3), 241; https://doi.org/10.3390/cells15030241 - 27 Jan 2026
Viewed by 549
Abstract
Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the [...] Read more.
Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the large 4a exon of approximately 250 amino acids. Big tau is predominantly expressed in neurons of the peripheral nervous system (PNS), cranial motor nuclei, and select neurons of the central nervous system (CNS) such as the cerebellum and brainstem. Developmental expression studies indicate a switch from low-molecular-weight isoforms of tau to Big tau during axonal maturation, suggesting that Big tau optimizes cytoskeletal dynamics to accommodate long axonal projections. Comparative sequence and biophysical analyses show that the exon-4a insert is highly acidic, intrinsically disordered, and evolutionarily conserved in its length but not its primary sequence, implying a structural role. Emerging modeling and in vitro assays suggest that the extended projection domain provided by the exon-4a insert spatially and electrostatically shields the aggregation-prone PHF6 and PHF6* motifs in tau’s microtubule-binding domain, thereby reducing β-sheet driven aggregation. This mechanism may explain why tauopathies that involve aggregation of tau have little effect on the PNS and specific regions of the CNS such as the cerebellum, where Big tau predominates. Transcriptomic and proteomic data further suggest that alternative Big tau variants, including 4a-L, are expressed in certain cancerous tissues, indicating broader roles in cytoskeletal remodeling beyond neurons. Despite its putative anti-aggregation properties, the physiological regulation, interaction partners, and in vivo mechanisms of Big tau remain poorly defined. This review summarizes what is known about Big tau and what is missing toward a better understanding of how expansion via inclusion of exon 4a modifies tau’s structural and functional properties. Our purpose is to inspire future studies that could lead to novel therapeutic strategies to mitigate tau aggregation in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Recent Advances in the Study of Tau Protein)
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37 pages, 801 KB  
Review
Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures
by Xinai Shen, Huan Li, Beiyu Zhang, Yunan Li and Zheying Zhu
Cells 2025, 14(19), 1506; https://doi.org/10.3390/cells14191506 - 26 Sep 2025
Cited by 4 | Viewed by 7199
Abstract
Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau’s normal functions, drive its mislocalization, and promote aggregation [...] Read more.
Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau’s normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies. Full article
(This article belongs to the Special Issue Recent Advances in the Study of Tau Protein)
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