Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F17%3A00065828" target="_blank" >RIV/00159816:_____/17:00065828 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016" target="_blank" >http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1523/JNEUROSCI.2305-16.2016" target="_blank" >10.1523/JNEUROSCI.2305-16.2016</a>

Result language

angličtina

Original language name

Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons

Original language description

Tau, as a microtubule-associated protein, participates in key neuronal functions such as the regulation of microtubule 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) microtubule binding repeats. While tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated to 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 question 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 trajectories 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. Contrarely, the imbalance towards 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 in APP dynamics, which might link tau isoforms imbalances with APP abnormal metabolism in neurodegenerative processes.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Neuroscience

ISSN

0270-6474

e-ISSN

—

Volume of the periodical

37

Issue of the periodical within the volume

1

Country of publishing house

US - UNITED STATES

Number of pages

12

Pages from-to

58-69

UT code for WoS article

000391143500006

EID of the result in the Scopus database

—