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Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay
The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been man...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225193/ https://www.ncbi.nlm.nih.gov/pubmed/30213139 http://dx.doi.org/10.3390/molecules23092335 |
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author | Holzer, Max Schade, Nico Opitz, Ansgar Hilbrich, Isabel Stieler, Jens Vogel, Tim Neukel, Valentina Oberstadt, Moritz Totzke, Frank Schächtele, Christoph Sippl, Wolfgang Hilgeroth, Andreas |
author_facet | Holzer, Max Schade, Nico Opitz, Ansgar Hilbrich, Isabel Stieler, Jens Vogel, Tim Neukel, Valentina Oberstadt, Moritz Totzke, Frank Schächtele, Christoph Sippl, Wolfgang Hilgeroth, Andreas |
author_sort | Holzer, Max |
collection | PubMed |
description | The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges. |
format | Online Article Text |
id | pubmed-6225193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62251932018-11-13 Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay Holzer, Max Schade, Nico Opitz, Ansgar Hilbrich, Isabel Stieler, Jens Vogel, Tim Neukel, Valentina Oberstadt, Moritz Totzke, Frank Schächtele, Christoph Sippl, Wolfgang Hilgeroth, Andreas Molecules Communication The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges. MDPI 2018-09-12 /pmc/articles/PMC6225193/ /pubmed/30213139 http://dx.doi.org/10.3390/molecules23092335 Text en © 2018 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Holzer, Max Schade, Nico Opitz, Ansgar Hilbrich, Isabel Stieler, Jens Vogel, Tim Neukel, Valentina Oberstadt, Moritz Totzke, Frank Schächtele, Christoph Sippl, Wolfgang Hilgeroth, Andreas Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title | Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_full | Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_fullStr | Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_full_unstemmed | Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_short | Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_sort | novel protein kinase inhibitors related to tau pathology modulate tau protein-self interaction using a luciferase complementation assay |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225193/ https://www.ncbi.nlm.nih.gov/pubmed/30213139 http://dx.doi.org/10.3390/molecules23092335 |
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