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 therapeuti...
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doaj-58995778edfc4af4b8e1cc0a3d2a0f3a2021-03-22T12:48:53ZengElsevierNeurobiology of Disease1095-953X2020-02-01134A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicityTravis Rush0Jonathan R. Roth1Samantha J. Thompson2Adam R. Aldaher3J. Nicholas Cochran4Erik D. Roberson5Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USACenter for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USACenter for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USACenter for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USACenter for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USACorresponding author at: University of Alabama at Birmingham, 1825 University Blvd, SHEL 1171, Birmingham, AL 35294, USA.; Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USAThe 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.http://www.sciencedirect.com/science/article/pii/S0969996119303432Amyloid-βOligomerTauSH3FynAlzheimer's disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Travis Rush Jonathan R. Roth Samantha J. Thompson Adam R. Aldaher J. Nicholas Cochran Erik D. Roberson |
spellingShingle |
Travis Rush Jonathan R. Roth Samantha J. Thompson Adam R. Aldaher J. Nicholas Cochran Erik D. Roberson A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity Neurobiology of Disease Amyloid-β Oligomer Tau SH3 Fyn Alzheimer's disease |
author_facet |
Travis Rush Jonathan R. Roth Samantha J. Thompson Adam R. Aldaher J. Nicholas Cochran Erik D. Roberson |
author_sort |
Travis Rush |
title |
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_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_sort |
peptide inhibitor of tau-sh3 interactions ameliorates amyloid-β toxicity |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2020-02-01 |
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. |
topic |
Amyloid-β Oligomer Tau SH3 Fyn Alzheimer's disease |
url |
http://www.sciencedirect.com/science/article/pii/S0969996119303432 |
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