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At least 811 records · Page 45Linked to original sources
PubMed1976

The significance of retrograde axonal transport for the accumulation of systemically administered nerve growth factor (NGF) in the rat superior cervical ganglion.

The present study has shown that after intravenous injection of [125I]NGF the time-course of appearance of radioactivity in all organs studied with the exception of sympathetic and sensory ganglia, roughly paralleled that of the blood. The highest levels were reached immediately after injection, after which the radioactivity decayed rapidly within the firsh hour. By contrast, in the superior cervical ganglion there was a small but significant increase within the first hour. After this the radioactivity remained constant for about 4 h and then increased dramatically (7-fold) when the radioactivity in other tissues had declined to very low levels. Measuring the proportion of radioactivity in the plasma which represents immunologically active NGF, we found that within 30 min after injection all the radioactivity represented unchanged [125I]NGF. After this time the proportion of immunologically active NGF decreased gradually and reached a final level of about 10-15%. Evidence that the radioactivity accumulated in the superior cervical ganglion by retrograde axonal transport represents unchanged [125I]NGF was provided by gel electrophoresis. The results are interpreted as follows: the initial small increase in the sympathetic ganglia may result either from [125I]NGF taken up by short collateral fibres within the ganglion or from a direct accumulation of blood-borne [125I]NGF by the cell bodies of the adrenergic neurones. The dramatic increase occurring after 4 h is caused by the moiety of [125I]NGF reaching the cell body by retrograde axonal transport. This interpretation is supported by autoradiographic studies which showed that 1 h after [125I]NGF injection there was only very sparse labelling of the ganglion, whereas 24 h later virtually all the cell bodies were heavily labelled. Moreover, it could be shown that the lag period between intravenous injection and subsequent accumulation of [125I]NGF in the adrenergic cell bodies was considerably shorter after transection of the postganglionic fibres distal to the cell body [the transected fibres were allowed to regenerate for 7 days] resulting in a reduction of the distance between the site of uptake and accumulation.

Animals↗
PubMed1974

The effect of nerve stimulation on the axonal transport of noradrenaline and dopamine-beta-hydroxylase.

1 A method for stimulating the lumbar sympathetic outflow from the spinal cord of the rat is described which does not require artificial respiration of the animal.2 In some, but not all experiments continuous stimulation at 2 Hz or intermittently at 10 Hz accelerated the rate at which noradrenaline and dopamine-beta-hydroxylase accumulated central to a ligature on the sciatic nerve by approximately 40%.3 It is concluded that, although nervous activity is not necessary for axonal transport of transmitter granules in sympathetic neurones, intense nervous activity may accelerate the rate of granule transport.

Animals↗
PubMed1985

Slow axonal transport in acrylamide neuropathy: different abnormalities produced by single-dose and continuous administration.

Alterations in axonal caliber and neurofilament content have been associated with altered neurofilament transport in several models of neurofibrillary degeneration. Acrylamide intoxication provides a prototype of distal axonal degeneration, the most frequent pattern of axonal pathology in human and experimental neurotoxic injury. Neurofibrillary changes are a variable and often minor aspect of the early pathological changes observed in acrylamide intoxication, and previous studies of slow axonal transport have produced conflicting results. In this study, we have correlated slow axonal transport, specifically neurofilament transport, with structural changes in the sciatic nerve complex of rats exposed to acrylamide. To study direct toxic effects of acrylamide, young rats were given a single dose of acrylamide (75 mg/kg, i.p.). A second group received daily injections of acrylamide at a lower dose (30 mg/kg, i.p.) in order to study animals with established acrylamide neuropathy. The slow component of axonal transport was labeled by intraspinal injections of [35S] methionine. Transport of individual slow component polypeptides was compared to profiles obtained from age-matched controls. Similarly intoxicated rats were perfused for morphometric and morphological studies. Results demonstrate that two different abnormalities of the slow component of axonal transport arise at different stages during the development of experimental acrylamide neuropathy. Both patterns of altered transport have structural correlates which reflect the changes in neurofilament transport. Following a single high dose, there was a modest retardation of the leading edge of the slow component. At this time, neurofilaments accumulated in proximal axons with formation of axonal swellings. During chronic administration, when distal axonal degeneration was present, the proportion of neurofilaments in the slow component was markedly reduced, and there was prominent loss of caliber in proximal axons. We suggest that these early changes represent a direct toxic effect of acrylamide on slow transport, whereas the later changes reflect reordering of slow transport as a neuronal response to toxin-induced axonal injury. This latter effect is of sufficient magnitude to obscure the acrylamide-induced retardation of slow transport.

Acrylamide↗
PubMed1998

Signalling events regulating the retrograde axonal transport of 125I-beta nerve growth factor in vivo.

The molecular mechanisms regulating the retrograde axonal transport of nerve growth factor (NGF) are currently unknown. This study identifies some of the signalling events involved. The phosphoinositide 3-kinase (PI3-kinase) inhibitor wortmannin (1 nmol/eye) irreversibly inhibits the amount of 125I-betaNGF retrogradely transported in both sensory and sympathetic neurons. Another PI3-kinase inhibitor LY294002 (100 nmol/eye) also inhibited 125I-betaNGF retrograde transport in sensory neurons. The pp70S6K inhibitor rapamycin (1 micromol/eye) had the same effect, inhibiting 125I-betaNGF transport only in sensory neurons. The cPLA2 inhibitor AACOCF3 (10 nmol/eye) had no effect on 125I-betaNGF transport in either sensory or sympathetic neurons. The TrkA receptor tyrosine kinase inhibitor AG-879 (10 nmol/eye) reduced 125I-betaNGF transport by approximately 50% in both sensory and sympathetic neurons. Cytochalasin D (2 nmol/eye), a disruptor of actin filaments and the dynein ATPase inhibitor erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA) both inhibited 125I-betaNGF retrograde transport. These results demonstrate that in vivo TrkA tyrosine kinase activity, actin filaments and dynein are involved in the retrograde transport of NGF. In addition, different PI3-kinase isoforms may be recruited within different neuronal populations to regulate the retrograde transport of NGF. Potentially, these isoforms could activate alternative signalling pathways, such as pp70S6K in sensory neurons.

Animals↗
PubMed1982

Presence and axonal transport of cholinoceptor, but not adrenoceptor sites on a cat noradrenergic neurone.

1. Noradrenaline release and radioligand binding studies were carried out in the cat hypogastric nerve ligated in vito 2 cm distal to the inferior mesenteric ganglion for different time periods, and in different effector organs.2. Large quantities of noradrenaline and dopamine beta-hydroxylase (DBH) accumulated in the segments of nerve immediately proximal (P(1)) and distal (D(1)) to the ligation, with rates of about 100 and 25 mm/24 hr for the orthograde and retrograde transport, respectively.3. Nicotine evoked the release of noradrenaline from P(1) and atrial slices; the secretory response to nicotine was completely antagonized by mecamylamine. [(3)H]alpha-bungarotoxin biding to membranes from P(1) allowed the estimation of a K(D) of 2.97 nm and a B(max) of 1639 f-mole/mg protein.4. Acetylcholine inhibited the release of endogenous noradrenaline evoked by high K(+) stimulation in atrial slices, but not in P(1) segments. Similarly, carbachol decreased [(3)H]noradrenaline release induced by electrical stimulation (twenty-six shocks, 2 Hz, 5 msec) in the atrium but not in P(1).5. [(3)H]Quinuclydinilbenzylate ([(3)H]QNB) specifically binds to membranes from P(1) and vas deferens, following a saturation curve. In the case of P(1) segments taken 48 hr after ligation a K(D) of 0.35 nm and a B(max) of 129 f-mole/mg protein were found.6. The fact that the B(max) in P(1) and D(1) increased with the time of ligation suggests that orthograde and retrograde axonal transports of muscarinic binding sites exist in this nerve, with approximate rates of transport of 15 and 8 mm/24 hr, respectively.7. As far as adrenoceptors are concerned, we observed that yohimbine or phentholamine did not modify transmitter release from P(1), evoked by high K(+) or electrical stimulation. However, yohimbine enhanced the release of [(3)H]noradrenaline induced by electrical stimulation from splenic slices of the same animals.8. [(3)H]Clonidine, [(3)H]dihydroergocryptine or [(3)H]dihydroalprenolol ([(3)H]DHA) did not specifically bind to membranes from P(1), in spite of the fact that they showed typical saturation curves for specific binding in cortex and atrial membranes from the same cats.9. In conclusion, these data (a) further show that the ligated hypogastric nerve is a good model of noradrenergic nerve terminal free of effector cell; (b) provide direct evidence for the neural location of nicotinic receptors whose activation trigger noradrenaline release from noradrenergic neurones; (c) demonstrate the neural location and axonal transport of muscarinic receptor sites, but leave certain doubts about its functional role in this noradrenergic neurone; and (d) do not support the hypothesis that alpha and beta-adrenoceptors which modulate noradrenaline release from peripheral noradrenergic nerve terminals are neurally (or prejunctionally) located.

Animals↗
PubMed1981

Is the retrograde axonal transport of 3H-5-HT a specific process of serotoninergic neurons?

The specificity of the retrograde axonal transport of 3H-serotonin (3H-5-HT) was radioautographically studied in the afferents to the olfactory bulb (O.B.). Injections of 3H-5-HT of different concentrations (10(-2), 10(-3), 10(-4) and 10(-5) M) were performed into the O.B. of catron pretreated rats. Following injection of 3H-5-HT (10(-2) M), a cytoplasmic perikaryal labeling was observed in the bulk of afferents to the O.B. (aminergic and non-aminergic neurons). When lower concentrations of 3H-5-HT (10(-5) M) were injected into the O.B., the retrograde labeling was only seen in the raphe dorsalis (RD) serotoninergic perikarya. The specificity of the uptake-retrograde transport of 3H-5-HT seems to depend on the selectivity of uptake by nerve terminals.

Afferent Pathways↗
PubMed1987

Retrograde axonal transport of mercury.

Female Wistar rats were injected in the tongue with a small volume of 203Hg and were killed 2 weeks later. The lower brain stem with the hypoglossal nuclei was removed and sectioned in a cryostat. Autoradiography of freeze-dried sections showed labeling of both hypoglossal nuclei. The results are regarded as strong evidence of retrograde axonal transport of mercury in the hypoglossal nerve.

Animals↗
PubMed1980

Axonal transport of the cytoskeleton in regenerating motor neurons: constancy and change.

We have examined slow axonal transport in regenerating motor neurons of the rat sciatic nerve. Using SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) we previously found that the slow component is the vehicle for the axonal cytoskeletal proteins, i.e. the neurofilament triplet proteins, tubulin and actin. When these proteins are pulse-labeled by injecting [3H]- or [35S]-amino acids into the spinal cord, they are transported distally in the nerve as two distinguishable waves of radioactivity, SCa and SCb. In normal motor neurons, the neurofilament triplet proteins and the tubulin are transported in SCa at an average velocity of 1.7 mm/day; the less heavily labeled SCb which moves at 2-5 mm/day is the primary vehicle for actin. We now find that during regeneration the velocity of SCa is unchanged in the region of the axon between the cell body and the lesion, but the amount of labeled neurofilament triplet and associated tubulin transported in the axon is decreased in neurons which had been labeled 20 days post-lesion. In contrast, the labeling of the slowly transported proteins moving ahead of the neurofilament triplet is greater in regenerating nerves than in controls. On the basis of our findings, we propose that in motor axons the normal supply of cytoskeletal protein, which is continuously transported in the slow component, is sufficient to support regeneration. Nevertheless, the neuron cell body can alter the supply of these cytoskeletal proteins so as to enhance its regenerative capacity.

Actins↗
PubMed1985

Specific changes in axonally transported proteins during regeneration of the frog (Xenopus laevis) optic nerve.

Labeled proteins in intact and regenerating optic nerves of juvenile Xenopus clawed frogs were examined at three different time points (2 to 4 hr, 18 hr, and 5 to 9 days) following [35S]methionine injection into the eye. The distal axon tips of optic nerves were transected at the margin of the tectal lobe and regeneration of the nerve was followed by three methods: autoradiography, tissue section counting following [3H]proline injection into the eye, and electrophysiological mapping of the visual field projection. By these methods, regrowth was found to occur 2 weeks after transection, but the fibers had not yet sorted their retinotopic pattern. Two-dimensional gel separation of labeled nerve proteins revealed 250 to 300 identifiable proteins, 89 of which (including all spots which differed consistently upon direct comparison of regenerating versus normal nerves) were selected for quantitative treatment. Nine of these spots (240, 135, 65, 64, 58, 54, 56, 31, and 26 kilodaltons) were shown to increase and six (56, 49, 42, 29, 17, and 15 kilodaltons) were shown to decrease significantly in regenerating nerves. By using a crush control and tracking the labeled proteins into the tectum over time, these proteins were shown to be axonally transported proteins. In addition, four other nonaxonally transported proteins also changed during regeneration.

Animals↗
PubMed2005

Neurofilaments can undergo axonal transport and cytoskeletal incorporation in a discontinuous manner.

Neurofilaments (NFs) are thought to provide structural support for axons. Some NFs exhibit an extended residence time along axons, the nature of which remains unclear. In prior studies in NB2a/d1 cells, hypophosphorylated NFs were demonstrated to be dispersed throughout the axon and to undergo relatively rapid axonal transport, while extensively phosphorylated NFs organized into a "bundle" localized along the center of the axon. It was not conclusively determined whether bundled NFs underwent transport or instead underwent turnover via exchange with transporting individual NFs. Herein, using transfection with multiple constructs and regional photobleaching, we demonstrate that bundled NFs undergo relatively slow transport as well as exchange with surrounding individual NFs. We also demonstrate that newly synthesized NFs disperse nonhomogenously throughout axonal neurites and perikarya. These findings provide a mechanism by which some NFs exhibit extended residence time within axons, which lessens the metabolic burden of cytoskeletal turnover.

Animals↗
PubMed1978

Subcellular fractionation of intra-axonally transport polypeptides in the rabbit visual system.

We analyzed the subcellular distributions of proteins that are transported down the axons of rabbit retinal ganglion cells and compared these distributions to those of enzyme markers for endoplasmic reticulum, plasma membrane, and mitochondria. The proteins of each of five previously identified transport groups were uniquely distributed through the subcellular fractions, suggesting that each transport group is associated with different subcellular organelles. In particular, all of the observed group I polypeptides (the most rapidly moving, group, maximum velocity greater than 240 mm/day) were associated with material of hydrodynamic properties similar to those of the plasma membrane. The proteins of group II (maximum velocity = 34--68 mm/day) were heterogenous in their subcellular distributions but included mitochondrial proteins. Groups III and IV (maximum velocity = 4--8 and 2--4 mm/day, respectively) included materials that may be involved in motile processes; group V (maximum velocity = 0.7--1.1 mm/day) contained material of very high density which may be associated with neurofilaments.

Animals↗
PubMed1987

Microtubule gelation-contraction: essential components and relation to slow axonal transport.

Preparations of microtubule proteins isolated by assembly and disassembly undergo gelation-contraction after addition of adenosine triphosphate (ATP). A particulate fraction from these preparations that is required, along with purified tubulin, to produce ATP-dependent microtubule gelation-contraction in vitro has been isolated. The particulates exhibited microtubule-stimulated adenosine triphosphatase activity and moved slowly (about 1 micrometer per minute) along microtubule walls in the presence of ATP. The particulates contained tubulin, neurofilament, and spectrin polypeptides. The composition, solubility, and motility of the particulates are consistent with those of slow component a of axonal transport.

Adenosine Triphosphatases↗
PubMed1985

Axonal transport of neurofilament proteins in IDPN neurotoxicity.

The neurofibrillary changes produced by IDPN are the consequence of the ability of the agent to impair the slow axonal transport of neurofilaments. The susceptibility of various neurons to this effect depends upon their neurofilament content; neurofilament-rich large caliber axons are severely affected. In motor neurons the half-velocities of neurofilament proteins are reduced 2-10 fold, while tubulin and other slow component constituents are only mildly altered. Optic nerve fibers are intermediate in vulnerability, and small neurofilament-poor fibers have little change in slow transport. The agent acts directly on the axon, and the transport defect is expressed all along the course of susceptible axons. Similar alterations in neurofilament transport have recently been found with 3,4-dimethyl-2,5-hexanedione, indicating that similar pathogenetic mechanisms can occur with toxic agents other than IDPN.

Animals↗
PubMed1993

Study of sympathetic innervation of cranial bones by axonal transport of horseradish peroxidase in the rat: preliminary findings.

This study performed by intraneuronal tracing directly demonstrates the presence of sympathetic postganglionic fibers in the cranial vault of the rat. Superior cervical sympathetic ganglia were injected with horseradish peroxidase (HRP), and after a 48-hour period, to permit anterograde axonal transport, the animals were sacrificed after in situ perfusion. An area of the calvaria that included portions of the frontal and parietal bones was fixed, decalcified and sectioned. HRP-containing axons were localized in the developing frontal and parietal bones of the calvaria. Adrenergic innervation was not demonstrated in sutural tissue (superior sagittal, coronal or metopic) by this technique. To our knowledge, this study is the first to trace sympathetic nerve fibers in the rat calvaria by intra-axonal transport of HRP.

Animals↗
PubMed1995

Generation of amyloidogenic C-terminal fragments during rapid axonal transport in vivo of beta-amyloid precursor protein in the optic nerve.

The amyloid beta-protein (A beta) is a major component of extracellular deposits that are characteristic features of Alzheimer's disease. A beta is derived from the large transmembrane beta-amyloid precursor protein (beta APP). In the rabbit optic nerve/optic tract (ON), beta APP is synthesized in vivo in retinal ganglion cell perikarya, rapidly transported into the ON axons in small transport vesicles and is subsequently transferred to the axonal plasma membrane as well as to the presynaptic nerve terminals (Morin, P. J., Abraham, C. R., Amaratunga, A., Johnson, R.J., Huber, G., Sandell, J. H., and Fine, R. E. (1993) J. Neurochem. 61, 464-473). Present results indicate that there is rapid processing of beta APP in the ON to generate a 14-kDa C-terminal membrane-associated fragment that contains the A beta sequence. By using equilibrium sucrose density gradient fractionation, this fragment, as well as non-amyloidogenic C-terminal fragments and intact beta APP, are detected in at least two classes of transport vesicles destined for the plasma membrane and the presynaptic nerve terminal. The two classes of transported vesicles are distinguished by labeling kinetics as well as by density. In contrast to the ON, only nonamyloidogenic C-terminal fragments are generated in the retina, which contains the perikarya of retinal ganglion cells and glial (Muller) cells which also produce beta APP.

Amyloid beta-Protein Precursor↗
PubMed1999

Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons.

Mutations in copper/zinc superoxide dismutase 1 (SOD1), primary causes of human amyotrophic lateral sclerosis (ALS), provoke motor neuron death through an unidentified toxic property. The known neurofilament-dependent slowing of axonal transport, combined with the prominent misaccumulation of neurofilaments in ALS, suggests that an important aspect of toxicity may arise from damage to transport. Here we verify this hypothesis for two SOD1 mutations linked to familial ALS. Reduced transport of selective cargoes of slow transport, especially tubulin, arises months before neurodegeneration. For one mutant, this represents the earliest detectable abnormality. Thus, damage to the cargoes or machinery of slow transport is an early feature of toxicity mediated by mutant SOD1.

Amyotrophic Lateral Sclerosis↗