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Exploring the Role of Tau Proteins in Alzheimer’s Disease from Typical Functioning MAPs to Aberrant Fibrillary Deposits in the Brain

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Deciphering Drug Targets for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory loss and cognitive function deficits in affected individuals, eventually affecting their motor functions. Among many other neurodegenerative conditions, AD is the leading cause of disability and dependency in the elderly population. The two principal essential markers of AD pathology include abnormal deposition neurofibrillary tangles (tau proteins) and amyloid plaques (Aβ peptides). Thus, tau proteins are of critical interest as the prominent indicator of disease mechanisms. Understanding the normal biological functions of tau and the role of PTMs (posttranslational modifications) is essential. In AD, the alteration of physiological tau proteins into aberrant misfolded proteins, such as oligomers, PHFs, and NFTs, due to the PTMs, leads to its interneuronal propagation along with Aβ plaques. It results in synapse loss, neurotoxicity, and neurodegeneration. Since extensive research has shown that Aβ-targeting medicines are toxic and less effective at attenuating AD pathology, tau-directed therapeutics have gained significant remedial focus in recent decades. Although current tau-related therapies provide transient symptomatic comfort, they do not treat the illness overall. Hence, modern research has focused on analyzing tau protein’s mechanisms and complexities to produce effective disease-modifying drugs. This review presents a thorough understanding of tau proteins in AD pathogenesis, their origin, and their essential roles in physiological conditions. Additionally, various effective therapeutics targeting tau-associated PTMs such as hyperphosphorylation, acetylation, and methylation are described. Moreover, novel therapeutic strategies such as immunotherapy and oligonucleotide therapy have been mentioned. The clinical trials surrounding tau-related medications have also been highlighted.

Graphical Abstract

The graphical abstract illustrates the pathological transformation of tau proteins to interneuronal fibrillary tangles (NFTs), due to posttranslational modifications, seen in AD.

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Abbreviations

AD :

Alzheimer’s disease

AIEC:

Anterolateral entorhinal cortex

APP :

Amyloid precursor protein

Aβ peptide:

Amyloid-beta peptide

CDK-5:

Cyclin-dependent kinases-5

CK1:

Casein kinase 1

COX:

Cyclooxygenase

CSF:

Cerebrospinal fluid

GSK-3:

Glycogen synthase kinase 3

HMTM:

Hydromethylthionine mesylate

JNK :

c-Jun N-terminal kinase

MAP:

Microtubule-associated proteins

MAP3K:

Mitogen-activated protein kinase

MAPT :

Microtubule-associated protein tau

MT:

Microtubules

MTBR:

Microtubule-binding region

NFT :

Neurofibrillary tangles

PHFs:

Paired helical filaments

PI3Ks:

Phosphoinositide 3-kinases

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

PMEC:

Posteromedial subregion

PP2A:

Protein phosphatase 2A

PTM:

Posttranslational modifications

SMAP:

Synthetic tricyclic sulfonamide PP2A activators

TG mice:

Transgenic mice

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Acknowledgement

All the schematic diagrams were made using Biorender.com software.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India

    Gadde Shareena

  2. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA

    Dileep Kumar

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  1. Gadde Shareena
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  2. Dileep Kumar
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Editors and Affiliations

  1. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA

    Dileep Kumar

  2. Department of Pharmaceutical Chemistry, KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India

    Vaishali M. Patil

  3. Department of Radiological Sciences, Section of Medical Physics, University of Oklahoma, Norman, OK, USA

    Dee Wu

  4. Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK

    Nanasaheb Thorat

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Authors’ Contributions: All authors contribute to the study conception and design.

Acknowledgements: The authors acknowledge support from the Principal of Poona College of Pharmacy, Pune.

Disclosure of Potential Conflicts of Interest: Not applicable.

Research Involving Human Participants and/or Animals: Not applicable.

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Shareena, G., Kumar, D. (2023). Exploring the Role of Tau Proteins in Alzheimer’s Disease from Typical Functioning MAPs to Aberrant Fibrillary Deposits in the Brain. In: Kumar, D., Patil, V.M., Wu, D., Thorat, N. (eds) Deciphering Drug Targets for Alzheimer’s Disease. Springer, Singapore. https://doi.org/10.1007/978-981-99-2657-2_14

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