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Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and as...

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Autores principales: Davidson, Ryder, Krider, Reese I., Borsellino, Philip, Noorda, Keith, Alhwayek, George, Vida, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670294/
https://www.ncbi.nlm.nih.gov/pubmed/37998730
http://dx.doi.org/10.3390/cimb45110553
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author Davidson, Ryder
Krider, Reese I.
Borsellino, Philip
Noorda, Keith
Alhwayek, George
Vida, Thomas A.
author_facet Davidson, Ryder
Krider, Reese I.
Borsellino, Philip
Noorda, Keith
Alhwayek, George
Vida, Thomas A.
author_sort Davidson, Ryder
collection PubMed
description Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.
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spelling pubmed-106702942023-11-02 Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies Davidson, Ryder Krider, Reese I. Borsellino, Philip Noorda, Keith Alhwayek, George Vida, Thomas A. Curr Issues Mol Biol Review Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases. MDPI 2023-11-02 /pmc/articles/PMC10670294/ /pubmed/37998730 http://dx.doi.org/10.3390/cimb45110553 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Davidson, Ryder
Krider, Reese I.
Borsellino, Philip
Noorda, Keith
Alhwayek, George
Vida, Thomas A.
Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title_full Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title_fullStr Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title_full_unstemmed Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title_short Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
title_sort untangling tau: molecular insights into neuroinflammation, pathophysiology, and emerging immunotherapies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670294/
https://www.ncbi.nlm.nih.gov/pubmed/37998730
http://dx.doi.org/10.3390/cimb45110553
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