Axonal Transport Rates In Vivo Are Unaffected by Tau Deletion or Overexpression in Mice

Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2008; 28(7):1682-7. DOI: 10.1523/JNEUROSCI.5242-07.2008
Source: PubMed


Elevated tau expression has been proposed as a possible basis for impaired axonal transport in Alzheimer's disease. To address this hypothesis, we analyzed the movement of pulse radiolabeled proteins in vivo along retinal ganglion cell (RGC) axons of mice that lack tau or overexpress human tau isoforms. Here, we show that the global axonal transport rates of slow and fast transport cargoes in axons are not significantly impaired when tau expression is eliminated or increased. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) do not accumulate in retinas and are distributed normally along optic axons in mice that lack or overexpress tau. Finally, ultrastructural analyses revealed no abnormal accumulations of vesicular organelles or neurofilaments in RGC perikarya or axons in mice overexpressing or lacking tau. These results suggest that tau is not essential for axonal transport and that transport rates in vivo are not significantly affected by substantial fluctuations in tau expression.

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    • "EFhd2 might also exert effects on dynein (MT minus end motor), specifically since differential regulation of dynein and kinesin motor proteins by locally altered concentrations of tau have been described earlier [38]. On the other hand, neither tau-deficient nor tau-overexpressing mice do show alterations of axonal transport in vivo [39]. Thus, alternatively and not mutually exclusive, EFhd2 might in neurons also interact with components of the actin cytoskeleton [8], [10], [40], like gelsolin does, which inhibits axonal transport in a Ca2+ dependent manner [41]. "
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    ABSTRACT: Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2-/- neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2-/- primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
    PLoS ONE 08/2014; 9(8):e103976. DOI:10.1371/journal.pone.0103976 · 3.23 Impact Factor
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    • "One major proposed function of tau, microtubule stabilization, is likely to have some redundancy from other microtubule-associated proteins such as MAP1B, since tau-/- mice are viable and fertile [8,9]. Tau has also been implicated in axonal transport, but loss of tau does not appear to impact on this cellular function [10-12]. However, loss of tau protein significantly delays the maturation of neurons, and affects the size of the cell body as well as the extent of dendritic arborization in primary cell culture [13,14]. "
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    ABSTRACT: Background We recently reported that Parkinsonian and dementia phenotypes emerge between 7-12 months of age in tau-/- mice on a Bl6/129sv mixed background. These observations were partially replicated by another group using pure Bl6 background tau-/- mice, but notably they did not observe a cognitive phenotype. A third group using Bl6 background tau-/- mice found cognitive impairment at 20-months of age. Results To reconcile the observations, here we considered the genetic, dietary and environmental variables in both studies, and performed an extended set of behavioral studies on 12-month old tau+/+, tau+/-, and tau-/- mice comparing Bl6/129sv to Bl6 backgrounds. We found that tau-/- in both backgrounds exhibited reduced tyrosine hydroxylase-positive nigral neuron and impaired motor function in all assays used, which was ameliorated by oral treatment with L-DOPA, and not confounded by changes in body weight. Tau-/- in the C57BL6/SV129 background exhibited deficits in the Y-maze cognition task, but the mice on the Bl6 background did not. Conclusions These results validate our previous report on the neurodegenerative phenotypes of aged tau-/- mice, and show that genetic background may impact the extent of cognitive impairment in these mice. Therefore excessive lowering of tau should be avoided in therapeutic strategies for AD.
    Molecular Neurodegeneration 08/2014; 9(1):29. DOI:10.1186/1750-1326-9-29 · 6.56 Impact Factor
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    • "In addition, a study demonstrated that WT human tau in a model lacking APP was enough to significantly worsen in vivo axonal transport deficits (Smith et al., 2010). Other studies have also demonstrated that axonal transport rates are unaffected by tau deletion or over-expression (Perez et al., 2013; Yuan et al., 2008). Furthermore, other studies using mouse models of tauopathy have implicated ex vivo deficits in axonal transport at late stages in disease progression post tau pathology (Zhang et al., 2004); (Zhang et al., 2010). "
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    ABSTRACT: Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4-5 months of age.
    Clinical neuroimaging 03/2014; 4. DOI:10.1016/j.nicl.2014.02.005 · 2.53 Impact Factor
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