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Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials

Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein des...

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Autores principales: Basheer, Neha, Smolek, Tomáš, Hassan, Imtaiyaz, Liu, Fei, Iqbal, Khalid, Zilka, Norbert, Novak, Petr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611587/
https://www.ncbi.nlm.nih.gov/pubmed/37264120
http://dx.doi.org/10.1038/s41380-023-02113-z
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author Basheer, Neha
Smolek, Tomáš
Hassan, Imtaiyaz
Liu, Fei
Iqbal, Khalid
Zilka, Norbert
Novak, Petr
author_facet Basheer, Neha
Smolek, Tomáš
Hassan, Imtaiyaz
Liu, Fei
Iqbal, Khalid
Zilka, Norbert
Novak, Petr
author_sort Basheer, Neha
collection PubMed
description Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer’s disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy.
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spelling pubmed-106115872023-10-29 Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials Basheer, Neha Smolek, Tomáš Hassan, Imtaiyaz Liu, Fei Iqbal, Khalid Zilka, Norbert Novak, Petr Mol Psychiatry Review Article Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer’s disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy. Nature Publishing Group UK 2023-06-02 2023 /pmc/articles/PMC10611587/ /pubmed/37264120 http://dx.doi.org/10.1038/s41380-023-02113-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’ks Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review Article
Basheer, Neha
Smolek, Tomáš
Hassan, Imtaiyaz
Liu, Fei
Iqbal, Khalid
Zilka, Norbert
Novak, Petr
Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title_full Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title_fullStr Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title_full_unstemmed Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title_short Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials
title_sort does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for alzheimer’s disease? from preclinical studies to the clinical trials
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611587/
https://www.ncbi.nlm.nih.gov/pubmed/37264120
http://dx.doi.org/10.1038/s41380-023-02113-z
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