Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783650191221456896 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7877553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT rushtravis apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT rothjonathanr apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT thompsonsamanthaj apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT aldaheradamr apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT cochranjnicholas apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT robersonerikd apeptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT rushtravis peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT rothjonathanr peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT thompsonsamanthaj peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT aldaheradamr peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT cochranjnicholas peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity AT robersonerikd peptideinhibitoroftaush3interactionsamelioratesamyloidbtoxicity |