2016
DOI: 10.1523/jneurosci.2305-16.2016
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Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons

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 mol… Show more

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Cited by 84 publications
(57 citation statements)
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“…This study extends the limited existing animal data based on brain homogenates to humans and demonstrates regional variation in tau expression that has not been previously described in humans or animals. Although the functional significance of the developmental switch in tau splicing remains unclear, its strong evolutionary conservation, and the fact that abnormalities in tau splicing have significant implications for axonal transport [ 44 ], amyloid processing [ 45 ] and the pathogenesis of human tauopathies [ 46 48 ] suggests that fetal isoform expression may play a necessary role in development while becoming toxic in the adult brain. Elucidating these functions will require more detailed animal and human studies.…”
Section: Discussionmentioning
confidence: 99%
“…This study extends the limited existing animal data based on brain homogenates to humans and demonstrates regional variation in tau expression that has not been previously described in humans or animals. Although the functional significance of the developmental switch in tau splicing remains unclear, its strong evolutionary conservation, and the fact that abnormalities in tau splicing have significant implications for axonal transport [ 44 ], amyloid processing [ 45 ] and the pathogenesis of human tauopathies [ 46 48 ] suggests that fetal isoform expression may play a necessary role in development while becoming toxic in the adult brain. Elucidating these functions will require more detailed animal and human studies.…”
Section: Discussionmentioning
confidence: 99%
“…Oligomeric α-Syn has also been shown to interfere directly with axonal transport by disrupting the association of kinesin-1 motors with microtubules ( Prots et al, 2013 ). The number of active motors interacting with microtubules is proposed as a mechanism that regulates transport velocity and directionality ( Leidel et al, 2012 ; Fu and Holzbaur, 2014 ; Lacovich et al, 2017 ). Interestingly, the velocity of microtubule gliding across kinesin-coated surfaces is significantly decreased in the presence of α-Syn oligomers ( Prots et al, 2013 ).…”
Section: A Role For α-Syn In Mitochondrial Dynamicsmentioning
confidence: 99%
“…In addition to recapitulating amyloid and tau changes, iPSCneurons from fAD patients have demonstrated a variety of cellular phenotypes including increased susceptibility to oxidative stress, abnormal endosomes and altered axonal transport (22,26,27). Whether any of these phenotypes can be rescued by modifying the levels or phosphorylation state of tau remains to be determined and will be an important area of future research.…”
Section: Modeling Tau Pathology In Ipsc-neurons From Admentioning
confidence: 99%