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Role of Tau in Various Tauopathies, Treatment Approaches, and Emerging Role of Nanotechnology in Neurodegenerative Disorders


A few protein kinases and phosphatases regulate tau protein phosphorylation and an imbalance in their enzyme activity results in tau hyper-phosphorylation. Aberrant tau phosphorylation causes tau to dissociate from the microtubules and clump together in the cytosol to form neurofibrillary tangles (NFTs), which lead to the progression of neurodegenerative disorders including Alzheimer’s disease (AD) and other tauopathies. Hence, targeting hyperphosphorylated tau protein is a restorative approach for treating neurodegenerative tauopathies. The cyclin-dependent kinase (Cdk5) and the glycogen synthase kinase (GSK3β) have both been implicated in aberrant tau hyperphosphorylation. The limited transport of drugs through the blood–brain barrier (BBB) for reaching the central nervous system (CNS) thus represents a significant problem in the development of drugs. Drug delivery systems based on nanocarriers help solve this problem. In this review, we discuss the tau protein, regulation of tau phosphorylation and abnormal hyperphosphorylation, drugs in use or under clinical trials, and treatment strategies for tauopathies based on the critical role of tau hyperphosphorylation in the pathogenesis of the disease.

Graphical Abstract

Pathology of neurodegenerative disease due to hyperphosphorylation and various therapeutic approaches including nanotechnology for its treatment.

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Data Availability

Not applicable as no datasets were generated or analysed during the current study.



Neurofibrillary tangles


Alzheimer’s disease


Parkinson’s disease


Cyclin-dependent kinase


Glycogen synthase kinase


Blood-brain barrier


Disability-adjusted life-years


Microtubule-associated protein tau FTDP-17, frontotemporal dementia associated with Parkinsonism having relation with chromosome 17


Progressive supranuclear palsy


Corticobasal degeneration


Pick’s disease


Argyrophilic grain disease


Globular glial tauopathy


Central nervous system


Isoelectric point


Terminal, amino-terminal


Terminal, carboxy-terminal


C-terminal region with three microtubule-binding repeats of 31 or 32 amino acids


C-terminal region with four microtubule-binding repeats of 31 or 32 amino acids


Nuclear magnetic resonance


Paired helical filaments








5′ Adenosine monophosphate-activated protein kinase


Microtubule affinity-regulating kinase


Protein phosphatase-1


Straight filaments




β-Amyloid precursor protein


Presenilin 1 gene


Presenilin 2 gene


Apolipoprotein E


Mammalian target of rapamycin


Substantia nigra pars compacta


Frontotemporal lobar degeneration


Microtubule-associated protein 1A/1B-light chain 3


Regulatory associated protein of mTOR


Mammalian lethal with Sec13 protein 8


40 KDa proline-rich AKT substrate


DEP-domain-containing mTOR-interacting protein


Rapamycin-insensitive companion of mTOR


Mammalian stress-activated protein kinase interacting protein


Protein observed with Rictor-1


Huntingtin, EF3, the A subunit of PP2A, TOR1


EIF4E-binding proteins




Tyrosine kinase inhibitors


European Medicines Agency


Activity-dependent neuroprotective protein


Tau aggregation inhibitor


Methylthioninium chloride




Leucomethylthioninium bis-hydromethanesulfonate


PP2A methyltransferase


Leucine carboxyl methyl transferase


PP2A methyl esterase


Single ascending dose


Common Alzheimer’s and Related Dementias Research Ontology


Mechanisms of action


Disease-modifying therapies


Clinical Dementia Rating scale Sum of Boxes


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We would like to thank Dr. Alisha Jones (Incoming Assistant Professor at NYU) for critically reading the manuscript. The authors gratefully acknowledge RPBlab and GSlab members for critical suggestions.


Our lab is supported by SERB, DBT and ICMR, Government of India, grants which are duly acknowledged. AK, HKA and AS are supported by UGC-JRF, DHR-YSS and ICMR-SRF fellowships, respectively.

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GS and RPB conceived the plan. PK, AK, and HKA wrote first draft. AS, PKJ, GS, and RPB edited and finalized the draft in coordination with other authors. All authors have approved it for publication.

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Correspondence to Gurpal Singh or Ravi P. Barnwal.

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• Neurological disorders are increasingly associated with fatalities globally.

• Tauopathies are mostly caused by hyperphosphorylation of tau protein.

• Drugs under development target pathways like mTOR, phosphorylation, and aggregation.

• Biomarkers for an early diagnosis like phosphorylated sites are in developmental stages.

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Kaur, P., Khera, A., Alajangi, H.K. et al. Role of Tau in Various Tauopathies, Treatment Approaches, and Emerging Role of Nanotechnology in Neurodegenerative Disorders. Mol Neurobiol 60, 1690–1720 (2023).

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