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

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Abstract

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.

Abbreviations

NFTs:

Neurofibrillary tangles

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

Cdk5:

Cyclin-dependent kinase

GSK3β:

Glycogen synthase kinase

BBB:

Blood-brain barrier

DALYs:

Disability-adjusted life-years

MAPT:

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

PSP:

Progressive supranuclear palsy

CBD:

Corticobasal degeneration

PiD:

Pick’s disease

AGD:

Argyrophilic grain disease

GGT:

Globular glial tauopathy

CNS:

Central nervous system

pI:

Isoelectric point

N:

Terminal, amino-terminal

C:

Terminal, carboxy-terminal

3R:

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

4R:

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

NMR:

Nuclear magnetic resonance

PHFs:

Paired helical filaments

Ser:

Serine

Thr:

Threonine

Tyr:

Tyrosine

AMPK:

5′ Adenosine monophosphate-activated protein kinase

MARK:

Microtubule affinity-regulating kinase

PP1:

Protein phosphatase-1

SFs:

Straight filaments

Aβ:

β-Amyloid

APP:

β-Amyloid precursor protein

PS1:

Presenilin 1 gene

PS2:

Presenilin 2 gene

APOE:

Apolipoprotein E

mTOR:

Mammalian target of rapamycin

SNpc:

Substantia nigra pars compacta

FTLD:

Frontotemporal lobar degeneration

LC3:

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

Raptor:

Regulatory associated protein of mTOR

mLST8:

Mammalian lethal with Sec13 protein 8

PRAS40:

40 KDa proline-rich AKT substrate

Deptor:

DEP-domain-containing mTOR-interacting protein

Rictor:

Rapamycin-insensitive companion of mTOR

mSIN1:

Mammalian stress-activated protein kinase interacting protein

Protor-1:

Protein observed with Rictor-1

HEAT:

Huntingtin, EF3, the A subunit of PP2A, TOR1

4EBPs:

EIF4E-binding proteins

IL-2:

Interleukin-2

TKIs:

Tyrosine kinase inhibitors

EMA:

European Medicines Agency

ADNP:

Activity-dependent neuroprotective protein

TAI:

Tau aggregation inhibitor

MTC:

Methylthioninium chloride

LMT:

Leuco-methylthioninum

LMTM:

Leucomethylthioninium bis-hydromethanesulfonate

PPMT:

PP2A methyltransferase

LCMT:

Leucine carboxyl methyl transferase

PME:

PP2A methyl esterase

SAD:

Single ascending dose

CADRO:

Common Alzheimer’s and Related Dementias Research Ontology

MOA:

Mechanisms of action

DMTs:

Disease-modifying therapies

CDR-SB:

Clinical Dementia Rating scale Sum of Boxes

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Acknowledgements

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.

Funding

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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Author notes

  1. Preetpal Kaur, Alisha Khera, and Hema K. Alajangi have equal contributions.

Authors and Affiliations

  1. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    Preetpal Kaur, Hema K. Alajangi, Akanksha Sharma & Gurpal Singh

  2. Department of Biophysics, Panjab University, Chandigarh, 160014, India

    Preetpal Kaur, Alisha Khera, Hema K. Alajangi, Akanksha Sharma & Ravi P. Barnwal

  3. National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind, Pune, Maharashtra, 411007, India

    Alisha Khera

  4. Department of Biochemistry and Biophysics, Texas A & M University, College Station, TX, 77843, USA

    Pradeep K. Jaiswal

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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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Highlights

• 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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Supplementary file1 (DOCX 24 KB)

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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). https://doi.org/10.1007/s12035-022-03164-z

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