Tau isoforms imbalance impairs the axonal transport of the amyloid precursor pro-tein (APP) in human neurons

VALENTINA LACOVICH; SONIA ESPINDOLA; MATIAS ALLOATTI; VICTORIO POZO DEVOTO; LUCAS CROMBERG; MARIA CARNA; GIANCARLO FORTE; JEAN MARK GALLO; LUCIANA BRUNO; GORAZD STOKIN; MARIA ELENA AVALE; TOMAS FALZONE

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2017

0270-6474

Abstract.Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in key cellular functions such as microtubule dynamics, axonal transport and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with either three (3R) or four (4R) microtubule binding repeats. During development human neurons express predominantly 3R tau, while the normal adult human brain reaches equal amounts of 3R and 4R isoforms. Intriguingly, 3R:4R imbalances have been tightly associated to the pathogenesis of several neurodegenerative disorders, however, the molecular mechanisms underlying this link with pathology remain to be elucidated. Several studies exploiting tau overexpression and/or mutations suggest that perturbations in tau metabolism produce deficits in axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of normal tau isoforms over axonal transport regulation. Here we addressed this question by analyzing the dynamics of the amyloid precursor protein (APP) by live imaging in human-derived neurons, in which endogenous tau isoform ratio was modulated using a trans-splicing strategy. We found that predominance of 3R tau favored the anterograde bias, affecting run lengths and reducing retrograde segmental velocities, while an imbalance towards 4R promoted a retrograde bias with reduction of anterograde segmental velocities without modifying the overall run lengths. These findings demonstrate a key role of 3R:4R tau isoform in the control of APP axonal transport, providing further evidence of the intimate link between tau and APP in driving neurodegeneration.