521 research outputs found
Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress
We studied the effect of microtubule-associated tau protein on trafficking of vesicles and organelles in primary cortical neurons, retinal ganglion cells, and neuroblastoma cells. Tau inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites. Loss of peroxisomes makes cells vulnerable to oxidative stress and leads to degeneration. In particular, tau inhibits transport of amyloid precursor protein (APP) into axons and dendrites, causing its accumulation in the cell body. APP tagged with yellow fluorescent protein and transfected by adenovirus associates with vesicles moving rapidly forward in the axon (∼80%) and slowly back (∼20%). Both movements are strongly inhibited by cotransfection with fluorescently tagged tau (cyan fluorescent protein–tau) as seen by two-color confocal microscopy. The data suggests a linkage between tau and APP trafficking, which may be significant in Alzheimer's disease
Inhibition of Tau aggregation with BSc3094 reduces Tau and decreases cognitive deficits in rTg4510 mice.
Background One of the major hallmarks of Alzheimer's disease (AD)is the aberrant modification and aggregation of the microtubule-associated protein Tau . The extent of Tau pathology correlates with cognitive decline, strongly implicating Tau in the pathogenesis of the disease. Because the inhibition of Tau aggregation may be a promising therapeutic target, we tested the efficacy of BSc3094, an inhibitor of Tau aggregation, in reducing Tau pathology and ameliorating the disease symptoms in transgenic mice. Methods Mice expressing human Tau with the P301L mutation (line rTg4510) were infused with BSc3094 into the lateral ventricle using Alzet osmotic pumps connected to a cannula that was placed on the skull of the mice, thus bypassing the blood-brain barrier (BBB) . The drug treatment lasted for 2 months, and the effect of BSc3094 on cognition and on reversing hallmarks of Tau pathology was assessed. Results BSc3094 significantly reduced the levels of Tau phosphorylation and sarkosyl-insoluble Tau. In addition, the drug improved cognition in different behavioral tasks and reduced anxiety-like behavior in the transgenic mice used in the study. Conclusions Our in vivo investigations demonstrated that BSc3094 is capable of partially reducing the pathological hallmarks typically observed in Tau transgenic mice, highlighting BSc3094 as a promising compound for a future therapeutic approach for AD
Structural impact of proline-directed pseudophosphorylation at AT8, AT100, and PHF1 epitopes on 441-residue tau.
Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation.
Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro.
Modeling oscillatory Microtubule--Polymerization
Polymerization of microtubules is ubiquitous in biological cells and under
certain conditions it becomes oscillatory in time. Here simple reaction models
are analyzed that capture such oscillations as well as the length distribution
of microtubules. We assume reaction conditions that are stationary over many
oscillation periods, and it is a Hopf bifurcation that leads to a persistent
oscillatory microtubule polymerization in these models. Analytical expressions
are derived for the threshold of the bifurcation and the oscillation frequency
in terms of reaction rates as well as typical trends of their parameter
dependence are presented. Both, a catastrophe rate that depends on the density
of {\it guanosine triphosphate} (GTP) liganded tubulin dimers and a delay
reaction, such as the depolymerization of shrinking microtubules or the decay
of oligomers, support oscillations. For a tubulin dimer concentration below the
threshold oscillatory microtubule polymerization occurs transiently on the
route to a stationary state, as shown by numerical solutions of the model
equations. Close to threshold a so--called amplitude equation is derived and it
is shown that the bifurcation to microtubule oscillations is supercritical.Comment: 21 pages and 12 figure
Nanomechanics of microtubules
We have determined the mechanical anisotropy of a single microtubule by simultaneously measuring the Young's and the shear moduli in vitro. This was achieved by elastically deforming the microtubule deposited on a substrate tailored by electron-beam lithography with a tip of an atomic force microscope. The shear modulus is 2 orders of magnitude lower than the Young's, giving rise to a length-dependent flexural rigidity of microtubules. The temperature dependence of the microtubule's bending stiffness in the (5-40) degreesC range shows a strong variation upon cooling coming from the increasing interaction between the protofilaments
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