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Lacovich, V.; Espindola, S.L.; Alloatti, M.; Devoto, V.P.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.M.; Bruno, L.; Stokin, X.B.; Avale, M.E.; Falzone, T.L. "Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons" (2017) Journal of Neuroscience. 37(1):58-69
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Abstract:

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.

Registro:

Documento: Artículo
Título:Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
Autor:Lacovich, V.; Espindola, S.L.; Alloatti, M.; Devoto, V.P.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.M.; Bruno, L.; Stokin, X.B.; Avale, M.E.; Falzone, T.L.
Filiación:Instituto de Biología Celular y Neurociencias (IBCN-CONICET-UBA), Facultad de Medicina Universidad de Buenos Aires, Buenos Aires, Argentina
Centre for Translational Medicine (CTM), International Clinical Research Center, St. Anne's University Hospital (ICRC-FNUSA), Brno, Czech Republic
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Buenos Aires, Argentina
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
Departamento de Física (IFIBA-CONICET), Facultad de Ciencias Exactas y Naturales (UBA), Buenos Aires, Argentina
Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
Palabras clave: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
Año:2017
Volumen:37
Número:1
Página de inicio:58
Página de fin:69
DOI: http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016
Título revista:Journal of Neuroscience
Título revista abreviado:J. Neurosci.
ISSN:02706474
CODEN:JNRSD
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v37_n1_p58_Lacovich

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Citas:

---------- APA ----------
Lacovich, V., Espindola, S.L., Alloatti, M., Devoto, V.P., Cromberg, L.E., Carna, M.E., Forte, G.,..., Falzone, T.L. (2017) . Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. Journal of Neuroscience, 37(1), 58-69.
http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016
---------- CHICAGO ----------
Lacovich, V., Espindola, S.L., Alloatti, M., Devoto, V.P., Cromberg, L.E., Carna, M.E., et al. "Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons" . Journal of Neuroscience 37, no. 1 (2017) : 58-69.
http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016
---------- MLA ----------
Lacovich, V., Espindola, S.L., Alloatti, M., Devoto, V.P., Cromberg, L.E., Carna, M.E., et al. "Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons" . Journal of Neuroscience, vol. 37, no. 1, 2017, pp. 58-69.
http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016
---------- VANCOUVER ----------
Lacovich, V., Espindola, S.L., Alloatti, M., Devoto, V.P., Cromberg, L.E., Carna, M.E., et al. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J. Neurosci. 2017;37(1):58-69.
http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016