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PubMedDate not supplied

Anterograde axonal transport, transcytosis, and recycling of neurotrophic factors: the concept of trophic currencies in neural networks.

Traditional views of neurotrophic factor biology held that trophic factors are released from target cells, retrogradely transported along their axons, and rapidly degraded upon arrival in cell bodies. Increasing evidence indicates that several trophic factors such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF-2), glial cell-line derived neurotrophic factor (GDNF), insulin-like growth factor (IGF-I), and neurotrophin-3 (NT-3), can move anterogradely along axons. They can escape the degradative pathway upon internalization and are recycled for future uses. Internalized ligands can move through intermediary cells by transcytosis, presumably by endocytosis via endosomes to the Golgi system, by trafficking of the factor to dendrites or by sorting into anterograde axonal transport with subsequent release from axon terminals and uptake by second- or third-order target neurons. Such data suggest the existence of multiple "trophic currencies," which may be used over several steps in neural networks to enable nurturing relationships between connected neurons or glial cells, not unlike currency exchanges between trading partners in the world economy. Functions of multistep transfer of trophic material through neural networks may include regulation of neuronal survival, differentiation of phenotypes and dendritic morphology, synapse plasticity, as well as excitatory neurotransmission. The molecular mechanisms of sorting, trafficking, and release of trophic factors from distinct neuronal compartments are important for an understanding of neurotrophism, but they present challenging tasks owing to the low levels of the endogenous factors.

Animals↗
PubMedDate not supplied

A novel brain ATPase with properties expected for the fast axonal transport motor.

Identification of the ATPase involved in fast axonal transport of membranous organelles has proven difficult. Myosin and dynein, other ATPases known to be involved in cell motility, have properties that are inconsistent with the established properties of fast axonal transport, an essential component of which is readily solubilized in physiological buffer conditions rather than being stably associated with either membranous organelles or cytoskeletal elements. Adenylyl imidodiphosphate (AMP-PNP), a nonhydrolysable analogue of ATP, is a potent inhibitor of fast axonal transport that results in a stable interaction of membranous organelles with microtubules. Here we report the identification and partial characterization of an ATPase activity from brain whose binding to microtubules is stabilized by AMP-PNP. This ATPase activity seems to be associated with a polypeptide of relative molecular mass (Mr) 130,000 that is highly enriched in microtubule pellets after incubation with AMP-PNP and a soluble fraction from chick brain. This novel ATPase fraction has the predicted characteristics of the motor involved in fast axonal transport. Common features between the ATPase and fast axonal transport include interaction with the cytoskeleton in the presence of AMP-PNP, ready extractability, no Ca2+ dependence and inhibition by EDTA.

Adenosine Triphosphatases↗
PubMed1982

Axonal transport and transcellular transfer of nucleosides and polyamines in intact and regenerating optic nerves of goldfish: speculation on the axonal regulation of periaxonal cell metabolism.

The axonal transport, metabolism, and transcellular transfer of uridine, adenosine, putrescine, and spermidine have been examined in intact and regenerating optic nerves of goldfish. Following intraocular injection of labeled nucleosides, axonal transport was determined by comparing left-right differences in tectal radioactivity, and transcellular transfer was indicated by light autoradiographic analysis. The results demonstrated axonal transport, transcellular transfer, and periaxonal cell utilization of both nucleosides in intact axons and severalfold increases of all of these processes in regenerating axons. Experiments in which the metabolism of the nucleosides was studied resulted in data which suggested that uridine and adenosine, when delivered to the tectum by axonal transport, are protected from degradation and thus are relatively more available for periaxonal cell utilization than nucleosides reaching these cells via the blood. In intact axons, the majority of the nonmetabolized radioactivity was present as UMP, UDP, and UTP following [3H]uridine injections, whereas the majority of the radioactivity following [3H]adenosine injections was present as adenosine, with the phosphorylated derivatives constituting a smaller proportion. During nerve regeneration, the relative proportion of nucleosides to nucleotides was reversed, with uridine being the principal labeled compound in the first case, and AMP, ADP, and ATP being the major labeled compounds in the latter case. The nucleosides also were found to be different from each other in that adenosine, but not uridine, can be taken up by optic axons and transported retrogradely from the tectum to retinal ganglion cell bodies in the eye. Following intraocular injection of [3H]spermidine, radioactivity was transported to the optic tectum and transferred to tectal cells in the vicinity of the regenerating axons. Following [3H]putrescine injections, silver grains were found over periaxonal glia, but preliminary findings suggest that they are not present over tectal neurons nor over radial glial cells in the periependymal layers. Analysis of tectal radioactivity showed in each case that it was composed primarily of the injected compounds. These studies indicate that, following axonal transport, the polyamines do not remain within regenerating axons but are transferred to cells surrounding the axon. On the basis of these and previous findings, we speculate that the axonal transport and transcellular transfer of uridine, adenosine, polyamines, and perhaps other small molecules are means of communication between axons and periaxonal cells; that the axon can affect RNA and protein synthesis in periaxonal cells by regulating the availability of these small molecules; and that, during nerve regeneration, the increased metabolic needs of periaxonal cells are met by an increased axonal supply of precursors (adenosine and uridine) and other molecules (polyamines) critical for protein synthesis.

Adenosine↗
PubMed1985

Cytoskeletal architecture and immunocytochemical localization of microtubule-associated proteins in regions of axons associated with rapid axonal transport: the beta,beta'-iminodipropionitrile-intoxicated axon as a model system.

Axons from rats treated with the neurotoxic agent beta,beta'-iminodipropionitrile (IDPN) were examined by quick-freeze, deep-etch electron microscopy. Microtubules formed bundles in the central region of the axons, whereas neurofilaments were segregated to the periphery. Most membrane-bounded organelles, presumably including those involved in rapid axonal transport, were associated with the microtubule domain. The high resolution provided by quick-freeze, deep-etch electron microscopy revealed that the microtubules were coated with an extensive network of fine strands that served both to cross-link the microtubules and to interconnect them with the membrane-bounded organelles. The strands were decorated with granular materials and were irregular in dimension. They appeared either singly or as an extensive anastomosing network in fresh axons. The microtubule-associated strands were observed in fresh, saponin-extracted, or aldehyde-fixed tissue. To explore further the identity of the microtubule-associated strands, microtubules purified from brain tissue and containing the high molecular weight microtubule-associated proteins MAP 1 and MAP 2 were examined by quick-freeze, deep-etch electron microscopy. The purified microtubules were connected by a network of strands quite similar in appearance to those observed in the IDPN axons. Control microtubule preparations consisting only of tubulin and lacking the MAPs were devoid of associated strands. To learn which of the MAPs were present in the microtubule bundles in the axon, sections of axons from IDPN-treated rats were examined by immunofluorescence microscopy using antibodies to MAP 1A, MAP 1B, MAP 2, and tubulin. Anti-MAP 2 staining was only marginally detectable in the IDPN-treated axons, consistent with earlier observations. Anti-MAP 1A and anti-MAP 1B brightly stained the IDPN-treated axons, with the staining exclusively limited to the microtubule domains. Furthermore, thin section-immunoelectron microscopy using colloidal gold-labeled second antibodies revealed that both anti-MAP 1A and anti-MAP 1B stained fuzzy filamentous structures between microtubules. In view of earlier work indicating that rapid transport is associated with the microtubule domain in the IDPN-treated axon, it now appears that MAP 1A and MAP 1B may play a role in this process. We believe that MAP 1A and MAP 1B are major components of the microtubule-associated fibrillar matrix in the axon.

Animals↗
PubMed1975

Absence of 'superfast' axonal transport in rat sciatic nerve.

Axonal transport of labelled protein was studied in rat sciatic nerve by analyzing nerve segments at intervals after injection of L-[3H]leucine into the lumbar spinal cord. Some nerves were sectioned before injection so that material in transit accumulated proximal to the section. The segments distal to the section served as controls for incorporation into the nerve of blood-borne label. An analysis of TCA-soluble and TCA-insoluble activity in cut and intact nerve segments was also made. No evidence was found for the existence of a 'superfast' component of axonal transport (velocity 2000 mm/day). Results showed that the most rapidly transported protein derived from the neuron soma had a conventional 'fast' velocity of 350-420 mm/day. There was no transport of TCA-soluble material. It is suggested that 'superfast' transport, detected in mice by other investigators, is an artefact resulting from failure to control for incorporation of circulating label into the sciatic nerve.

Animals↗
PubMed2005

Axonal transport of the cellular prion protein is increased during axon regeneration.

The cellular prion protein, PrPc, is a glycosylphosphatidylinositol-anchored cell surface glycoprotein and a protease-resistant conformer of the protein may be the infectious agent in transmissible spongiform encephalopathies. PrPc is localized on growing axons in vitro and along fibre bundles that contain elongating axons in developing and adult brain. To determine whether the growth state of axons influenced the expression and axonal transport of PrPc, we examined changes in the protein following post-traumatic regeneration in the hamster sciatic nerve. Our results show (1) that PrPc in nerve is significantly increased during nerve regeneration; (2) that this increase involves an increase in axonally transported PrPc; and (3) that the PrPc preferentially targeted for the newly formed portions of the regenerating axons consists of higher molecular weight glycoforms. These results raise the possibility that PrPc may play a role in the growth of axons in vivo, perhaps as an adhesion molecule interacting with the extracellular environment through specialized glycosylation.

Animals↗
PubMed1978

Kinetic properties of normal and perturbed axonal transport of serotonin in a single identified axon.

1. The axonal transport of pulses of [3H]serotonin was studied in an axon of the serotonergic giant cerebral neurone (GCN) of Aplysia californica. 2. [3H]serotonin was transported as a discrete peak which was followed by a relatively low, smooth trail. 3. The peak broadened as it moved along the axon, sometimes skewing in the proximal direction. 4. The velocity of the transport was highly dependent on temperature, but the rate of peak broadening was not. The velocity was 130 mm per day at 23 degrees C and 48 mm per day at 14 degrees C. The rate of broadening was 143 micrometer per mm transport at 23 degrees C and 156 micrometer per mm transport at 14 degrees C. 5. In another series of experiments, almost the entire length of the lip nerve, which contained the axon of GCN, was maintained at 1--3 degrees C to block transport. The GCN's cell body and the proximal few millimetres of the nerve were maintained at 23 degrees C. As a result, the amount of [3H]serotonin in the proximal segment of the nerve increased manyfold during periods of up to 4 hr. The concentrated pulse of [3H]serotonin resulting from this treatment was transported more slowly than normal after the cooling was terminated. Sometimes, a minor peak split from the major peak of radioactivity and was transported a normal velocity. 6. Incubation of the cerebral ganglion and nerves for 16 hr in the presence of anisomycin, an inhibitor of protein synthesis, reduced by nearly fourfold the amount of [3H]serotonin subsequently exported into the axon of the GCN. The transport velocity at this reduced concentration was less than half the normal value. If the concentration of [3H]serotonin in the axon was restored to normal in the presence of anisomycin, the velocity of transport was also returned to normal. 7. We conclude that the velocity of transport of serotonergic vesicles in the axon of the GCN is positively dependent on the local concentration of vesicles, except at very high concentrations, where the dependence is negative. The results are interpreted in the context of a model for transport in which the serotonergic vesicle is translocated along the axon in an intermittent fashion, alternating between moving and stationary states. The local concentration of the vesicles along the axon would control the observed velocity of transport by altering the partitioning between the two states, that is, by changing the percentage of time vesicles spend in each state.

Animals↗
PubMed1977

The relation of axonal transport of mitochondria with microtubules and other axoplasmic organelles.

Axonal transport of mitochondria was studied in frog sciatic nerves incubated in agents selected for their known or alleged effect on microtubules or axonal flow. Quantitative data on mitochondria, microtubules, neurofilaments, endoplasmic reticulum, and cross-sectional area of the axon indicate that axonal transport of mitochondria is dependent on microtubules. When more than half of the microtubules are destroyed, the axonal transport of mitochondria is diminished in proportion to the destruction of microtubules. Axonal transport of mitochondria is not related to neurofilaments and endoplasmic reticulum. Changes in the cross-sectional area of axons, even upon reduction to half the normal size, do not noticeably affect mitochondrial transport. Cyanide which blocks oxidative metabolism also blocks axonal transport of mitochondria, but analysis of fine structure indicates that cyanide is destructive to microtubules as well.

Animals↗
PubMed1985

Proteins transported in slow components a and b of axonal transport are distributed differently in the transverse plane of the axon.

The distribution of the proteins migrating with the slow components a (SCa) and b (SCb) of axonal transport were studied in cross-sections of axons with electron microscope autoradiography. Radiolabeled amino acids were injected into the hypoglossal nucleus of rabbits and after 15 d, the animals were killed. Hypoglossal nerves were processed either for SDS-polyacrylamide gel electrophoresis fluorography to identify and locate the two components of slow transport, or for quantitative electron microscope autoradiography. Proteins transported in SCa were found to be uniformly distributed within the cross-section of the axon. Labeled SCb proteins were also found throughout the axonal cross-section, but the subaxolemmal region of the axon contained 2.5 times more SCb radioactivity than any comparable area in the remainder of the axon.

Actins↗
PubMed1981

Impairment of protein synthesis in the retinal tissue in diabetic rabbits: secondary reduction of fast axonal transport.

Protein biosynthesis in the retina and fast axonal transport along the optic pathway were studied in rabbits in which diabetes had been experimentally induced. Retinal protein biosynthesis and axonal transport were significantly reduced in the diabetic rabbits, and the reduction was correlated to the severity of the diabetes. The "somal delay time' was only slightly elongated and the O/R ratio was fairly constant in the various levels of blood glucose; thus intrasomal protein movement seems to be less affected in diabetic rabbits. Velocity and the distribution pattern of axonally transported protein remained unaffected in the diabetic rabbits. These findings suggest that a disturbance in the metabolism in the cell body is the most important factor related to quantitative reduction of fast axonal transport in diabetic rabbits.

Animals↗
PubMed1974

The retrograde axonal transport of nerve growth factor.

A retrograde axonal transport of nerve growth factor (NGF) from the adrenergic nerve terminals in the mouse iris to the cell bodies of postganglionic sympathetic neurones in the superior cervical ganglion has been demonstrated. After injection of iodinated nerve growth factor (125I-NGF) into the anterior eye-chamber there was a relatively rapid accumulation of radioactivity in the superior cervical ganglia on both injected and non-injected sides, as was the case after subcutaneous injection. However, 4 h after intraocular injection a preferential accumulation of radioactivity became apparent in the superior cervical ganglion on the injected side, and this difference between the ganglia on injected and non-injected sides gradually increased to a maximum at 16 h. Transection of the postganglionic adrenergic fibres as well as the prior intraocular injection of colchicine abolished the preferential accumulation of 125I-NGF in the superior cervical ganglion of the injected side, whereas the destruction of adrenergic nerve terminals by 6-hydroxydopamine did not impair the preferential accumulation. It is concluded that the retrograde axonal transport of NGF, which was estimated to take place at a rate of about 2.5 mm/h, depends on a colchicine-sensitive mechanism as does the orthograde rapid axonal transport. However, the uptake of NGF may not only take place from the nerve terminals but also from the preterminal parts, as has been shown in other studies with horseradish peroxidase. Autoradiographic studies strongly supported the existence of a retrograde transport by showing a clear localization of radioactivity in a small number of neurones in the superior cervical ganglion on the injected side, whereas on the non-injected side there was only a diffuse distribution of radioactivity throughout the ganglion.

Animals↗
PubMed2003

Anterograde axonal transport of endopeptidase 24.15 in rat sciatic nerves.

Axonal transport of endopeptidase 24.15 (EP24.15), a putative neuropeptide degrading-enzyme, was examined in the proximal, middle, and distal segments of rat sciatic nerves using a double ligation technique. At 48h after ligation, a significant amount of the axonal transport of EP24.15 activity was found in the proximal segment, while axonal transport of deamidase activity, a lysosomal enzyme, increased in both proximal and distal segments. Western blot analysis of EP24.15 showed that EP24.15 immunoreactivity in the proximal segment was 1.8-fold higher than that in the middle segment. The immunohistochemical analysis of the segments also showed an increase in the immunoreactive EP24.15 in the proximal segment in comparison with that in the middle segment. In the distal segment, no axonal transport of EP24.15 was found in all methods examined, indicating that EP24.15 is mainly transported by an anterograde axonal flow. These observations suggest that EP24.15 may be involved in the metabolism of neuropeptides in nerve terminals or synaptic clefts.

Animals↗
PubMed1987

Differential growth of the branches of a regenerating bifurcate axon is associated with differential axonal transport of organelles.

Axonal trees display differential growth during development or regeneration; that is, some branches stop growing and often retract while other branches continue to grow and form stable synaptic connections. In this study, an in vitro model of differential growth is examined to identify the intracellular events responsible for this phenomenon. When the giant cerebral neuron of Aplysia californica is placed in culture, vigorous growth occurs from the ends of both branches of its bifurcate axon. If an appropriate target neuron is placed next to one branch, growth from that branch is unabated while growth from the other branch is suppressed. The bidirectional fast transport of membranous organelles was examined in the two branches by the use of high-resolution video microscopy. Transport was similar in the branches in the absence of a target cell but was much greater in the growing than in the nongrowing branch when a target was present. Electron microscopic examination of fixed specimens confirmed these findings. Differential growth may be initiated or sustained by a diversion from certain branches of materials used in growth which are supplied by fast axonal transport.

Animals↗
PubMed1983

Localization of axonally transported 125I-wheat germ agglutinin beneath the plasma membrane of chick retinal ganglion cells.

The distribution of 125I-wheat germ agglutinin (WGA) transported by axons of chick retinal ganglion cells to layer d of the optic tectum was studied by electron microscopic autoradiography. We found that 52% of the radioactivity was located in axons and axon terminals in the contralateral optic tectum 22 h after intravitreal injection of affinity-purified 125I-WGA. Axons comprised 43% of the volume of layer d. Dendrites, glial cells, and neuron cell bodies contained 20%, 17%, and 3% of the label, whereas these structures comprised 24%, 21%, and 2% of the tissue volume, respectively. We also measured the distances between the autoradiographic silver grains and the plasma membranes of these profiles, and compared observed distributions of grains to theoretical distributions computed for band-shaped sources at various distances from the plasma membranes. This analysis revealed that the radioactive source within axons was distributed in a band of cytoplasm extending in from the plasma membrane a distance of 63 nm. Because WGA is known to bind to specific membrane glycoconjugates, we infer that at least some glycoconjugates may be concentrated within an annular region of cytoplasm just beneath the axonal plasma membrane after axoplasmic transport from the neuron cell body.

Animals↗
PubMed1995

Anterograde to retrograde reversal of fast axonal transport within cold blocked and rewarmed intact axons.

The possibility that anterograde to retrograde reversal of axonal transport might take place in mid axon at a site distant from any nerve termination was investigated in sciatic nerve preparations from Xenopus laevis. The nerve, containing a pulse of anterogradely transported protein labeled with [35S]methionine, was kept in a two-compartment temperature controlled chamber. One compartment containing the proximal nerve was maintained at room temperature throughout the duration of an experiment while the second compartment containing the distal nerve, and separated from the first by a thermal barrier, was initially cooled to 3-4 degrees C and later warmed to room temperature. Transport of labeled proteins in the nerve was detected with a position-sensitive detector of ionizing radiation. With the distal portion of the nerve cold, the pulse of labeled protein transported up to the thermal barrier and stopped. When the distal part of the nerve was warmed to room temperature, retrograde and anterograde pulses of label propagated away from the thermal barrier with no time delay. The retrograde pulse could be collected on the distal side of a proximally placed tie and could be eliminated by treatment of the proximal nerve with vinblastine or dinitrophenol. Functional and structural evidence indicated that the cold block and thermal barrier were not destructive to the axons. Electron microscopy showed that the numerical density of axonal microtubules distal to the cold block was decreased about seven fold during the cold treatment and that this decrease could be prevented by 10 mumol/l taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Age-related changes in axonal transport.

In rats the rate of axonal transport (AT) or radiolabeled material decreased in the ventral roots of the spinal cord and the vagal and hypoglossal nerves with aging. A maximum AT deceleration in old age was observed in the vagus. The uncoupling of oxidative phosphorylation, inhibition of glycolysis and hypoxia induced a greater AT deceleration in old rats as compared to adults. Small doses of sodium fluoride accelerated AT, and this correlated with a rise in cAMP levels in ventral roots. High doses of sodium fluoride decelerated AT more markedly in old rats. It was shown that anabolic hormones (sex steroids and thyroxine) accelerated AT in both adult and old rats, whereas insulin induced a rise in AT rate in only adults. The catabolic steroid, hydrocortisone decelerated AT. In old rats castration diminished AT, while thyroidectomy had no effect. It was also shown that hydrocortisone and testosterone were transported along axons, reached fibers of the skeletal muscles, and hyperpolarized the plasma membrane. In old age the latent period was extended. Following 73 to 74 days of irradiation, AT slowed down in all the nerves studied in both adult and old rats. Following irradiation hormonal effects on AT changed, for example, the stimulatory effect of estradiol became weak, especially in old rats. Changes in AT could be an important mechanism of disordering the growth of neurons and innervated cells in old age.

Aging↗
PubMedDate not supplied

Microtubule motors, phosphorylation and axonal transport of neurofilaments.

The recent demonstration that the axonal transport motors kinesin and dynein participate in axonal transport of neurofilaments (NFs), and that the association of NFs with these motors is regulated by phosphorylation provides new insight into several aspects of axonal transport and NF biology. This review juxtaposes older and more recent findings on NF dynamics, and speculates on the organization of axonal NFs as suggested by real-time analyses of NF transport.

Animals↗
PubMedDate not supplied

Retrograde axonal transport in chronic ethanol-fed and thiamine-deficient rats.

Retrograde axonal transport may play an important role in the feedback regulation of protein synthesis in neuronal perikarya, and the anterograde axonal transport of protein. The "dying-back" neuropathies associated with thiamine deficiency and chronic alcoholism may arise as a consequence of altered axonal transport. We have reported alterations in fast anterograde axonal transport in rats as a result of ethanol exposure or thiamine deficiency. The present studies were undertaken to determine whether retrograde transport was also affected by these experimental treatments. One group of rats was fed a liquid diet containing 6.7% ethanol for 16 weeks. Another group of rats was made thiamine deficient with a thiamine-free diet for 4 weeks. Retrograde axonal transport was labeled by injecting the left sciatic nerve unilaterally with 3H-N-succinimidyl propionate. This compound covalently labels proteins in the nerve at the site of injection and is accumulated by retrograde axonal transport to sensory nerve cell bodies in the dorsal root ganglia and motor nerve cell bodies in the spinal cord. After 7 days, dorsal root ganglia of chronic ethanol-fed rats showed a significant 45% decrease in the amount of accumulated retrograde label compared to controls. No significant differences in accumulation were found in the spinal cords. These results suggest that the peripheral neuropathies caused by chronic alcoholism and thiamine deficiency follow different etiologies, and that motor and sensory fibers are affected differently by ethanol.

Animals↗