Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding r...
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2017
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v37_n1_p58_Lacovich http://hdl.handle.net/20.500.12110/paper_02706474_v37_n1_p58_Lacovich |
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paper:paper_02706474_v37_n1_p58_Lacovich2023-06-08T15:24:53Z Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons Alzheimer's APP Axonal transport Splicing Tau Tauopathies amyloid precursor protein tau protein anterograde regulation Article cell culture controlled study electrokymography genetic transduction genetic transfection human human cell human embryonic stem cell imaging immunofluorescence modulation nerve cell nerve cell differentiation nerve fiber transport nervous system parameters optical density plating medium polarization polymerase chain reaction priority journal retrograde regulation Western blotting Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. 2017 the authors. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v37_n1_p58_Lacovich http://hdl.handle.net/20.500.12110/paper_02706474_v37_n1_p58_Lacovich |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Alzheimer's APP Axonal transport Splicing Tau Tauopathies amyloid precursor protein tau protein anterograde regulation Article cell culture controlled study electrokymography genetic transduction genetic transfection human human cell human embryonic stem cell imaging immunofluorescence modulation nerve cell nerve cell differentiation nerve fiber transport nervous system parameters optical density plating medium polarization polymerase chain reaction priority journal retrograde regulation Western blotting |
| spellingShingle |
Alzheimer's APP Axonal transport Splicing Tau Tauopathies amyloid precursor protein tau protein anterograde regulation Article cell culture controlled study electrokymography genetic transduction genetic transfection human human cell human embryonic stem cell imaging immunofluorescence modulation nerve cell nerve cell differentiation nerve fiber transport nervous system parameters optical density plating medium polarization polymerase chain reaction priority journal retrograde regulation Western blotting Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| topic_facet |
Alzheimer's APP Axonal transport Splicing Tau Tauopathies amyloid precursor protein tau protein anterograde regulation Article cell culture controlled study electrokymography genetic transduction genetic transfection human human cell human embryonic stem cell imaging immunofluorescence modulation nerve cell nerve cell differentiation nerve fiber transport nervous system parameters optical density plating medium polarization polymerase chain reaction priority journal retrograde regulation Western blotting |
| description |
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. 2017 the authors. |
| title |
Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| title_short |
Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| title_full |
Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| title_fullStr |
Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| title_full_unstemmed |
Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| title_sort |
tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v37_n1_p58_Lacovich http://hdl.handle.net/20.500.12110/paper_02706474_v37_n1_p58_Lacovich |
| _version_ |
1768545373073178624 |