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Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the ext...

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Autores principales: Melchiorri, Daniela, Merlo, Sara, Micallef, Benjamin, Borg, John-Joseph, Dráfi, František
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272781/
https://www.ncbi.nlm.nih.gov/pubmed/37332353
http://dx.doi.org/10.3389/fphar.2023.1196413
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author Melchiorri, Daniela
Merlo, Sara
Micallef, Benjamin
Borg, John-Joseph
Dráfi, František
author_facet Melchiorri, Daniela
Merlo, Sara
Micallef, Benjamin
Borg, John-Joseph
Dráfi, František
author_sort Melchiorri, Daniela
collection PubMed
description Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.
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spelling pubmed-102727812023-06-17 Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy? Melchiorri, Daniela Merlo, Sara Micallef, Benjamin Borg, John-Joseph Dráfi, František Front Pharmacol Pharmacology Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed. Frontiers Media S.A. 2023-06-02 /pmc/articles/PMC10272781/ /pubmed/37332353 http://dx.doi.org/10.3389/fphar.2023.1196413 Text en Copyright © 2023 Melchiorri, Merlo, Micallef, Borg and Dráfi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Melchiorri, Daniela
Merlo, Sara
Micallef, Benjamin
Borg, John-Joseph
Dráfi, František
Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title_full Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title_fullStr Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title_full_unstemmed Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title_short Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
title_sort alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272781/
https://www.ncbi.nlm.nih.gov/pubmed/37332353
http://dx.doi.org/10.3389/fphar.2023.1196413
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