Author/Editor		Lacovich, Valentina; Espindola, Sonia L.; Alloatti, Matías; Pozo Devoto, Victorio Martin; Cromberg, Lucas E.; Čarná, Mária; Forte, Giancarlo; Gallo, Jean-Marc; Bruno, Luciana; Stokin, Gorazd Bernard
Title		Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
Type		članek
Vol. and No.		Letnik 37, št. 1
Publication year		2017
Volume		str. 58-69
ISSN		0270-6474 - The Journal of neuroscience : the official journal of the Society for Neuroscience
Language		eng
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 in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.
Keywords		Alzheimer's disease axonal transport neurodegenerative processes Alzheimerjeva bolezen aksonski transport nevrodegenerativni procesi