. Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci. 2008 Feb 13;28(7):1682-7. PubMed.

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  1. Reply by Aidong Yuan and Ralph Nixon to comments
    Our study was an in vivo test of the hypothesis that moderate overexpression of tau directly impairs axonal transport. We expected our in vivo results to support in vitro data, but the surprising absence of a significant effect was clear and is compatible with existing data. The thoughtful comments in this forum highlight important general issues for consideration in future investigations in this area. As discussed in our report, we agree with the view expressed by Fred Van Leuven that our findings do not exclude the possibility that pathological states of tau might directly or indirectly alter axonal transport. Going forward, however, the task of defining any meaningful direct connection between pathological tau and transport disruption will require that primary effects on transport be distinguished from indirect effects that are secondary to neurodegeneration, which inevitably disrupts transport. In the studies of mice overexpressing tau 4R cited by Van Leuven (1-4), the inference that axonal transport may be disrupted is based on neuropathological detection of focal organelle accumulations in the degenerating axons of tg mice. While the conclusion may well be correct, evidence from the only one of these studies that investigated axonal transport directly (3) suggests that effects on transport in this case are more likely secondary to neurodegeneration than related to a primary effect of tau 4R on transport mechanisms.

    In these time-lapse transport analyses of fluorescent dextran-loaded vesicles in DRG axons of tau 4R tg mice, “the calculated mean of absolute velocities of fluorescent vesicles moving >0.1 μm/min reveals that both retrograde and anterograde vesicle transport did not differ significantly between transgenic and control mice” (3). Also, in vivo tracking of fluorescent vesicle numbers after intranerve injection of fluorescent dextran in live mice showed that tau 4R and wt mice differed at 1 hour, but not at 2 hours or 3 hours (3). Therefore, in the one context where axonal transport was measured directly, overexpression of tau 4R had no or equivocal effects on transport velocities. This observation is consistent with our data and with the Alzforum comment of Akihiko Takashima that “if tau overexpression induces impairment of axonal transport, tau tg mice must show neuronal dysfunction in the entire brain from a young age on” and not only after 20 months of age, when aging-related factors might combine with tau cytotoxicity to cause axonal degeneration and secondary transport failure. Rescue of this pathology by GSK-3β overexpression in tau 4R mice (4) may well be directly related to tau hyperphosphorylation, although neuroprotection could also involve reversal of transport-independent cytotoxic effects of tau.

    We agree with Virginia Lee and John Trojanowski that our results are compatible with findings from their labs. The overexpression of the shortest isoform of tau at levels that were higher than those in our study was associated with neurofibrillary degeneration and reduced fast transport rates measured directly in vivo in side-by-side comparisons with appropriate control groups. Our discussion of these studies was not a misread of the two papers we cited (5-6). It instead drew attention to a comparison specifically of the untreated (or sham-treated) tau tg mice across the two studies showing that the range of fast transport rates for these tg mice overlapped with the rate measured for wt mice. Regardless of the precise extent of transport impairment, this model features significant neurofibrillary degeneration unlike the model we studied, as they pointed out. If high tau levels have direct effects on transport in this model, it would need to be shown in the absence of indirect effects on transport arising from tau-mediated neurodegeneration.

    The Alzforum comments and data from in vivo and in vitro studies emphasize that the degree of tau overexpression is critical to any observed effects on axonal transport. Transport impairments have been associated so far only with very high tau expression, although Fred Van Leuven points out that the emergence of pathological effects at any level of tau overexpression may be influenced by additional vulnerabilities of the animal contributed by genotype and phenotype. Finally, any observed effect of tau at altered expression levels will need to be evaluated in the light of disease relevance, namely, clear evidence that tau levels are comparably altered in Alzheimer disease or other tauopathies. Existing evidence on this issue is not so clear.

    References:

    . Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. PubMed.

    . Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. PubMed.

    . Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau. J Neurosci. 2002 Sep 1;22(17):7471-7. PubMed.

    . Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol. 2006 Aug;169(2):599-616. PubMed.

    . Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):227-31. PubMed.

    . Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron. 1999 Nov;24(3):751-62. PubMed.

  2. This interesting paper uses classical assays to measure slow transport and some markers for fast axonal transport. It sees no differences in gross rates of axonal transport in the absence of tau, or upon tau overexpression. Thus, this work differs significantly from observations made by the Mandelkow lab looking at the effects of tau expression on axonal transport and organelle localization.

    The reasons for the apparent discrepancies between these observations remain to be determined. One possibility is the nature of the cargos under investigation, as the paper by Yuan et al. is focusing primarily on cargos undergoing slow transport along the axon. An alternate possibility is the relatively insensitive nature of the transport assay used by Yuan et al. For example, previous work using this approach in the SOD1 model for familial ALS did not reveal significant defects in anterograde transport until relatively late in disease (Zhang et al., 1997; Williamson and Cleveland, 1999), whereas live cell assays for vesicular transport that we have done on neurons from the SOD1 mouse (Perlson et al., submitted) do reveal significant changes in transport velocities. Alternatively, isoform expression may affect the observations, as we and others have seen pronounced differences in the effects of tau isoforms on microtubule motors at the single molecule level.

    In our recent work on the differential effects of tau on kinesin and dynein (Dixit et al., 2008), the motility of individual kinesin motors was strongly affected when the motors encountered patches of tau bound along the microtubule. These encounters most frequently resulted in either pausing of the motor or detachment of the kinesin from the microtubule. It is possible that for larger cargos undergoing longer-distance transport, these molecular-level changes are damped out. This is an interesting question that needs to be investigated further with high-resolution assays. Alternatively, as Yuan et al. suggest, there may be compensatory mechanisms operating in vivo that mitigate the effects seen at the molecular level.

    Thus, their argument is a good one: we need to keep examining in vivo biology in concert with higher-resolution studies that offer more mechanistic insights.

    References:

    . Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol. 1997 Dec 1;139(5):1307-15. PubMed.

    . Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999 Jan;2(1):50-6. PubMed.

    . Differential regulation of dynein and kinesin motor proteins by tau. Science. 2008 Feb 22;319(5866):1086-9. PubMed.