Article

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

ABSTRACT

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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    • "High levels of tau accumulation are detected in the axonal region near the synapse [54], which may facilitate cargo delivery to presynaptic terminals [51]. Moreover, while several observations suggest that removal or overexpression of tau in vitro or in vivo does not impair axonal transport [55] [56], other studies suggest that overexpression of wild-type or mutant tau in either cell or mice models of tauopathy impairs axonal transport [57] [58]. These discrepancies may be due to differences in study design or model systems used. "
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    ABSTRACT: Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer’s disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of the MAPT gene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxidative stress, but microglial cells were recently identified as reactive oxygen species producers in tauopathies. Here we review the complex relationships between tau pathology and oxidative stress, placing emphasis on (i) tau protein function, (ii) origin and consequences of reactive oxygen species production, and (iii) links between tau phosphorylation and oxidative stress. Further, we go on to discuss the hypothesis that tau hyperphosphorylation and oxidative stress are two key components of a vicious circle, crucial in neurodegenerative tauopathies.
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    • "Neuronal axon–Schwann cell interaction(s) are essential for myelination, and myelin maintenance is a dynamic process tightly controlled by axondependent transcription factors such as Krox20 and Oct6 (Murphy et al., 1996; Decker et al., 2006). In line with previous studies demonstrating an absence of axonal deficits in neurons of TauÀ/À animals (Yuan et al., 2008; Vossel et al., 2010), there were no differences in mRNA levels of transcription factors that critically regulate myelination process and/or maintenance, for example, Krox20 and Oct6 (data not shown), suggesting no gross changes in myelin gene regulation of TauÀ/À Schwann cells. Furthermore, supporting the involvement of Tau and other cytoskeletal elements in myelination process, previous evidence suggests that Tau strongly colocalizes with MBP in distal tips of oligodendrocytes (LoPresti et al., 1995; Muller et al., 1997), suggesting that transportation and/or local MBP translation may require microtubule cytoskeleton and might be controlled by Tau–Fyn interaction (Klein et al., 2002). "
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    ABSTRACT: Dementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well-established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor-related tests, we herein provide evidence of an age-dependent motor impairment in Tau-/- animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor-related information. Specifically, we show that the sciatic nerve of old (17-22-months) Tau-/- mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age-matched wild-type (Tau+/+) littermates and younger (4-6 months) Tau-/- and Tau+/+ mice. In addition, the sciatic nerves of Tau-/- mice exhibit a progressive hypomyelination (assessed by g-ratio) specifically affecting large-diameter, motor-related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.
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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.
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