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A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity

The microtubule-associated protein Tau is strongly implicated in Alzheimer’s disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic tar...

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Autores principales: Rush, Travis, Roth, Jonathan R., Thompson, Samantha J., Aldaher, Adam R., Cochran, J. Nicholas, Roberson, Erik D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877553/
https://www.ncbi.nlm.nih.gov/pubmed/31698056
http://dx.doi.org/10.1016/j.nbd.2019.104668
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author Rush, Travis
Roth, Jonathan R.
Thompson, Samantha J.
Aldaher, Adam R.
Cochran, J. Nicholas
Roberson, Erik D.
author_facet Rush, Travis
Roth, Jonathan R.
Thompson, Samantha J.
Aldaher, Adam R.
Cochran, J. Nicholas
Roberson, Erik D.
author_sort Rush, Travis
collection PubMed
description The microtubule-associated protein Tau is strongly implicated in Alzheimer’s disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Tau’s interactions with Fyn kinase and other SH3 domain–containing proteins, which bind to PxxP motifs in Tau’s proline-rich domain, may contribute to AD deficits and Aβ toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates Aβ toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated Aβ oligomer (Aβo)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated Aβo toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyn’s kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated Aβo toxicity by multiple outcome measures, namely Aβo-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for Aβo toxicity and that inhibiting them is a promising therapeutic target for AD.
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spelling pubmed-78775532021-02-11 A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity Rush, Travis Roth, Jonathan R. Thompson, Samantha J. Aldaher, Adam R. Cochran, J. Nicholas Roberson, Erik D. Neurobiol Dis Article The microtubule-associated protein Tau is strongly implicated in Alzheimer’s disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Tau’s interactions with Fyn kinase and other SH3 domain–containing proteins, which bind to PxxP motifs in Tau’s proline-rich domain, may contribute to AD deficits and Aβ toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates Aβ toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated Aβ oligomer (Aβo)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated Aβo toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyn’s kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated Aβo toxicity by multiple outcome measures, namely Aβo-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for Aβo toxicity and that inhibiting them is a promising therapeutic target for AD. 2019-11-05 2020-02 /pmc/articles/PMC7877553/ /pubmed/31698056 http://dx.doi.org/10.1016/j.nbd.2019.104668 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Rush, Travis
Roth, Jonathan R.
Thompson, Samantha J.
Aldaher, Adam R.
Cochran, J. Nicholas
Roberson, Erik D.
A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title_full A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title_fullStr A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title_full_unstemmed A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title_short A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
title_sort peptide inhibitor of tau-sh3 interactions ameliorates amyloid-β toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877553/
https://www.ncbi.nlm.nih.gov/pubmed/31698056
http://dx.doi.org/10.1016/j.nbd.2019.104668
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