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PubMed1986

Retrograde axonal transport of [125I]nerve growth factor in ileal mesenteric nerves in vitro: effect of streptozotocin diabetes.

The retrograde axonal transport of intravenously administered [125I]nerve growth factor ([125I]NGF) was examined in ileal mesenteric nerves maintained for short periods in vitro. [125I]NGF was injected systemically, and at various times thereafter mesenteric pedicles were ligated and incubated in vitro in Krebs-Henseleit medium under a number of different conditions. Retrogradely transported [125I]NGF began to accumulate distal to the ligature after an initial lag period and increased in a linear fashion for 3-4 h. The amount of retrogradely transported [125I]NGF was proportional to the length of the ileum innervated by each pedicle, which allowed for comparison of ileal segments of different lengths. Retrograde axonal transport of [125I]NGF was inhibited by vinblastine, colchicine and incubation in the cold, and was decreased by agents that interfere with oxidative or glycolytic metabolism. The accumulation of retrogradely transported [125I]NGF in ileal mesenteric nerves of 1-9 day streptozotocin diabetic animals placed in an in vitro bath containing normal (5.5 mM) glucose was decreased 40% compared to control animals. The induction of diabetes in vivo resulted in a greater decrease in the early phases of [125I]NGF export from ileal mesenteric nerve terminals compared to later phases. Ileal mesenteric nerve segments derived from untreated controls were incubated in vitro in media containing increased concentrations of glucose (27.5 and 50 mM) without reproducing the NGF transport defect found in diabetic animals.

Animals↗
PubMed1977

The intra-axonal transport of polypeptide H: evidence for a fifth (very slow) group of transported proteins in the retinal ganglion cells of the rabbit.

We have determined that a genetically polymorphic polypeptide (H, molecular weight approximately equal to 195,000) of the rabbit nervous system is transported down the retinal ganglion cell axons at a velocity of 0.7-1.1 mm/day. The H-polypeptide and probably at least two additional polypeptides (molecular weights approximately 145,000 and 73,000) therefore compose a group of intra-axonally transported proteins which moves more slowly than the 4 groups previously described in these neurons. The polypeptides of this fifth group are similar in molecular weight to certain polypeptides transported slowly in other mammalian neurons.

Animals↗
PubMed1988

Ganglioside treatment of streptozotocin-diabetic rats prevents defective axonal transport of 6-phosphofructokinase activity.

This study measured axonal transport of 6-phosphofructokinase (PFK) and aldolase activities in the sciatic nerves of rats with short-term streptozotocin-induced diabetes. The diabetic rats showed deficits in anterograde (69% of controls; p less than 0.001) and retrograde (33% of controls; p less than 0.01) accumulations of PFK activity as well as its content per unit length of unconstricted sciatic nerve (86% of controls; p less than 0.05). There were no accumulation deficits in aldolase activity in the nerves of the diabetic rats, although the activity per unit length of unconstricted nerve was deficient (81% of controls; p less than 0.05). Treatment of diabetic rats with mixed bovine brain gangliosides (10 mg/kg of body weight/day, i.p.) did not affect the deficit in PFK activity in unconstricted nerve (84% of ganglioside-treated controls; p less than 0.01), but all the other defects in enzyme activities were prevented completely. The diabetic rats also showed a reduction of 7% (p less than 0.01) in sciatic nerve dry weight per unit length, which was prevented by ganglioside treatment. In contrast, the reduced motor nerve conduction velocity, accumulation of polyol pathway metabolites, and depletion of myo-inositol, characteristic of untreated short-term diabetes, were unaffected by ganglioside treatment.

Animals↗
PubMed1979

Evidence that 4S RNA is axonally transported in normal and regenerating rat sciatic nerves.

Studies in regenerating goldfish optic nerves indicate that RNA may be axonally transported during optic nerve regeneration14,18,19. The present study was performed to determine if the axonal migration of RNA could be demonstrated during regeneration of the rat sciatic nerve. Rats, which had only the left sciatic nerve crushed 10 days earlier, were injected bilaterally with [3H]uridine into the spinal cord at segmental levels L5 and L6, thus labeling ventral horn cells giving rise to the sciatic nerve. Six, 14 and 20 days later rats were sacrificed by cardiac perfusion of saline followed by 10% formaldehyde. Formaldehyde-precipitable radioactivity, identified as [3H]RNA, was 4--5 times greater in the regenerating sciatic nerve compared to the normal nerve and moved without impediment beyond the point of the crush into the regenerating portion of the nerve. The axonal migration of free unincorporated labeled RNA precursors was also demonstrated, raising the possibility that the distribution of [3H]RNA along the sciatic nerve might be entirely extra-axonal; i.e., free [3H]uridine is taken up by Schwann cells from the axon where it is incorporated into [3H]RNA. This interpretation of the data would also result in the appearance of a proximodistal distribution of RNA associated radioactivity. To determine whether any sciatic nerve [3H]RNA was due to axonal transport, rats which had only the left sciatic nerve crushed 10 days earlier were injected bilaterally with [3H]uridine into the spinal cord. Fourteen days after injection, rats were sacrificed and radioactivity present in the nerve was confirmed as RNA by SDS polyacrylamide gel electrophoresis. Radioactivity in the various RNA species 14 days after intraspinal injection showed the following distribution: 28 + 18S RNA--normal 39.3% +/- 2.1; regenerating 45.4% +/- 1.6; 4S RNA--normal 43.0% +/- 1.3; regenerating 46.8% +/- 2.7. Similar characterization of sciatic nerve RNA 1 or 3 days following the intravenous administration of [3H]uridine gave the following distribution: 28 + 18S RNA--normal 72.4% +/- 3.0; regenerating 75.0% +/- 3.6; 4S RNA--normal 7.7% +/- 1.3; regenerating 10.7% +/- 0.8. The intraspinal injection of [3H]uridine would label Schwann cell RNA and, in addition, any species of intra-axonal RNA, while intravenous injections would label Schwann cell RNA and not axonal RNA. If 4S RNA is in the axon, one would predict relatively more labeled 4S RNA following intraspinal injections than following intravenous injections. The data demonstrate an enrichment of 4S RNA in both normal and regenerating rat sciatic nerve following the intraspinal but not following the intravenous injection of labeled precursor. Therefore, we suggest that 4S RNA migrates axonally in both normal and regenerating sciatic nerves of rats.

Animals↗
PubMed1998

Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms.

We investigated the retrograde axonal transport of 125I-labeled neurotrophins (NGF, BDNF, NT-3, and NT-4) from the sciatic nerve to dorsal root ganglion (DRG) sensory neurons and spinal motor neurons in normal rats or after neuronal injury. DRG neurons showed increased transport of all neurotrophins following crush injury to the sciatic nerve. This was maximal 1 day after sciatic nerve crush and returned to control levels after 7 days. 125I-BDNF transport from sciatic nerve was elevated with injection either proximal to the lesion or directly into the crush site and after transection of the dorsal roots. All neurotrophin transport was receptor-mediated and consistent with neurotrophin binding to the low-affinity neurotrophin receptor (LNR) or Trk receptors. However, transport of 125I-labeled wheat germ agglutinin also increased 1 day after sciatic nerve crush, showing that increased uptake and transport is a generalized response to injury in DRG sensory neurons. Spinal cord motor neurons also showed increased neurotrophin transport following sciatic nerve injury, although this was maximal after 3 days. The transport of 125I-NGF depended on the expression of LNR by injured motor neurons, as demonstrated by competition experiments with unlabeled neurotrophins. The absence of TrkA in normal motor neurons or after axotomy was confirmed by immunostaining and in situ hybridization. Thus, increased transport of neurotrophic factors after neuronal injury is due to multiple receptor-mediated mechanisms including general increases in axonal transport capacity.

Animals↗
PubMed2001

Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila.

We tested the hypothesis that amyloid precursor protein (APP) and its relatives function as vesicular receptor proteins for kinesin-I. Deletion of the Drosophila APP-like gene (Appl) or overexpression of human APP695 or APPL constructs caused axonal transport phenotypes similar to kinesin and dynein mutants. Genetic reduction of kinesin-I expression enhanced while genetic reduction of dynein expression suppressed these phenotypes. Deletion of the C terminus of APP695 or APPL, including the kinesin binding region, disrupted axonal transport of APP695 and APPL and abolished the organelle accumulation phenotype. Neuronal apoptosis was induced only by overexpression of constructs containing both the C-terminal and Abeta regions of APP695. We discuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed1992

Slow axonal transport of soluble proteins and calpain in retinal ganglion cells of aged rabbits.

The rate of slow axonal transport of soluble proteins in retinal ganglion cells of the rabbit decreased with approximately 25% in aged (6 years) compared to previous estimates in adult (2 years) animals. Immunobinding of calpain to microtiter plates coated with a monoclonal antibody to mu-calpain was used to isolate labelled axonally transported mu-calpain from the nerve extracts. It was found that the distribution of labelled mu-calpain in the retrobulbar optic pathway was similar to the distribution profile of the slowly migrating phase of soluble proteins.

Aging↗
PubMed1976

Inhibition and stimulation of rapid axonal transport in vitro by sulfhydryl blockers.

The effects of sulfhydryl blocking agents have been studied on the rapid axonal transport in vitro of [3H]leucine-labelled proteins in the frog sciatic nerve. The transport was inhibited in the presence of low concentrations of N-ethylmaleimide (NEM) (greater than or equal to 10(-5) M), p-chloromercuribenzene sulfonic acid (PCMBS) (greater than 10(-5) M) or ions of heavy metals, Cd2+ (greater than or equal to 5 X 10(-5) M), Hg2+ (greater than or equal to 5 X 10(-6) M) and Cu2+(greater than or equal to 10(-4) M). Both the amount and the rate of transported radioactivity were reduced. Transport inhibiting concentrations of these agents also inhibited the binding of colchicine in rat brain or frog nerve supernatants. The amount of transported proteins was increased at an unchanged transport rate by a very low concentration of NEM (10(-6) M), PCMBS (10(-6) M) and Cd2+ (10(-6)M), which did not affect the binding of colchicine. The present results suggest that stimulation of axonal transport can be achieved through an interaction with sulfhydryl groups.

4-Chloromercuribenzenesulfonate↗
PubMed1984

Consequences of axonal transport blockade by batrachotoxin on mammalian neuromuscular junction. III. An ultrastructural study.

Ultrastructural alterations were analyzed following a single subperineural injection of batrachotoxin (BTX) into the rat peroneal nerve 10-12 mm proximal to its entrance into the extensor digitorum longus (EDL) muscle. At the injection site, most axons underwent reversible changes. Internodal segments of myelin degenerated and were phagocytized without apparent damage to the axon cylinders. Newly forming myelin sheaths were observed by 10 days after injection. Similarly, motor endplates were reversibly altered. By 18 h following injection, most nerve terminals were withdrawn from the postsynaptic elements but reinnervated original endplate regions between 7 and 10 days after injection. These observations explain earlier findings in which muscle membrane potential decreased immediately and spontaneous miniature endplate potentials (MEPPs) and evoked transmitter release were absent from 18 h to 7 days following injection. We suggest that these reversible changes were the result of an insufficient supply of neuronal materials due to BTX-induced blockade of fast axonal transport. Normal physiological function and morphology were restored after fast axonal transport recovered and sufficient quantities of appropriate materials necessary for the maintenance of the nerve terminals and muscle membrane potential were again transported distally from the nerve cell body.

Animals↗
PubMed2000

Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I.

We analyzed the mechanism of axonal transport of the amyloid precursor protein (APP), which plays a major role in the development of Alzheimer's disease. Coimmunoprecipitation, sucrose gradient, and direct in vitro binding demonstrated that APP forms a complex with the microtubule motor, conventional kinesin (kinesin-I), by binding directly to the TPR domain of the kinesin light chain (KLC) subunit. The estimated apparent Kd for binding is 15-20 nM, with a binding stoichiometry of two APP per KLC. In addition, association of APP with microtubules and axonal transport of APP is greatly decreased in a gene-targeted mouse mutant of the neuronally enriched KLC1 gene. We propose that one of the normal functions of APP may be as a membrane cargo receptor for kinesin-I and that KLC is important for kinesin-I-driven transport of APP into axons.

Alzheimer Disease↗
PubMed1987

Penfluridol, chlorprothixene and haloperidol block fast axonal transport in an order of potency consistent with a mechanism related to inhibition of calmodulin.

The effects of the inhibitors of calmodulin penfluridol, chlorprothixene and haloperidol on fast axonal transport, the content of adenosine triphosphate and creatine phosphate and the density of axonal microtubules, were measured in spinal nerves of the bullfrog in vitro. These drugs inhibited the fast orthograde transport of [3H]leucine-labelled proteins: 35 microM penfluridol, 70 microM cis-chlorprothixene, and 200 microM haloperidol were needed to produce and approximately 50% inhibition of transport, and the order of potency was, therefore, penfluridol greater than cis-chlorprothixene greater than haloperidol; the trans isomer of chlorprothixene was as effective as the cis isomer-of chlorprothixene in inhibiting fast axonal transport. None of these drugs significantly reduced the density of microtubules in unmyelinated axons of nerves, incubated as for a transport experiment. Exposure to the concentration of these drugs which inhibited transport did not reduce significantly the content of adenosine triphosphate of the nerves, except for a 22% reduction by trans-chlorprothixene, and they had no significant effect on the content of creatine phosphate except for a 27% reduction by penfluridol and a 20% reduction by trans-chlorprothixene. The inhibition of axonal transport by these drugs can therefore not be explained either by an interference with oxidative metabolism or by disruption of microtubules. The order of potency of penfluridol, chlorprothixene and haloperidol as inhibitors of fast axonal transport parallels their known order of potency as antagonists of calmodulin; inhibition of axonal transport may therefore be related to inhibition of the function of calmodulin by these drugs.

Adenosine Triphosphate↗
PubMed1986

Prevention of defects of axonal transport in experimental diabetes by aldose reductase inhibitors.

Experiments on streptozotocin-diabetic rats have indicated that axonal transport of choline acetyltransferase is reduced in sciatic nerve. Treatment with an aldose reductase inhibitor both prevented and reversed this defect which was related to marked accumulations of sorbitol and fructose. Concurrent with these accumulations the content of myo-inositol in diabetic peripheral nerve is depleted. Further experiments taking account of nerve water content showed that the depletion of myo-inositol was 'real' not apparent. When the level of myo-inositol was maintained, either by feeding myo-inositol or by the inhibition of aldose reductase, the development of defective axonal transport of choline acetyltransferase and choline-containing lipids was prevented.

Aldehyde Reductase↗
PubMed1988

Axonal transport of choline acetyltransferase and 6-phosphofructokinase activities in genetically diabetic mice.

This study examined the anterograde axonal transport of activities of the cytoplasmic enzymes choline acetyltransferase and 6-phosphofructokinase in genetically diabetic C57BL/Ks (db/db) mice and their nondiabetic (+/?) littermates. Diabetic mice exhibited marked reductions in the accumulation of both choline acetyltransferase and 6-phosphofructokinase activity against a constriction of the left sciatic nerve (38% and 51% of nondiabetic values, respectively). Enzyme activities per unit length of unconstricted nerve were not different from those of nondiabetic mice. The nerves of diabetic mice did not accumulate measurable amounts of sorbitol or fructose and showed no myo-inositol depletion. Thus this study concludes that, in diabetic mice, the deficits in anterograde axonal transport of these two enzymes do not arise from the accumulation of sorbitol and fructose nor from depletion of nerve free myo-inositol.

Animals↗
PubMed1995

Retrograde axonal transport of signal transduction proteins in rat sciatic nerve.

Neurons require a mechanism to transmit stable signals over the large distance from the nerve growth cone or terminal to the cell body, in order that information from the target tissue can be relayed to the cell body where it is required. Nerve growth factor (NGF), a target-derived neurotrophic factor, is thought to signal over this distance by receptor mediated internalization of NGF, followed by retrograde axonal transport of the NGF-receptor complex. In this paper we show, by immunohistochemistry of rat sciatic nerve, accumulation of phosphotyrosine immunoreactivity only on the distal side of a nerve crush, suggesting axonal transport of tyrosine kinases and/or tyrosine phosphorylated proteins primarily in a retrograde direction. Furthermore, we also show retrograde axonal transport of phosphoinositide 3-kinase, ERK, MEK and MEK kinase, of which all but MEK kinase are known to be activated downstream of tyrosine receptor kinase activation. The retrograde transport of these proteins suggests that they may be involved in transmission of signals along the axon, relaying neurotrophic factor receptor activation at the nerve terminal to the nerve cell body.

Animals↗
PubMed1987

Enhanced visualization of axonally transported proteins in the immature CNS by suppression of systemic labeling.

In the neonate hamster, visualization of axonally transported proteins in the retinofugal pathway is obscured by high levels of systemic (background) labeling. Radiolabeled precursors injected into the eye diffuse rapidly into the general circulation and then across the immature blood-brain barrier to be incorporated into proteins that are synthesized throughout the brain. Systemic labeling can be suppressed, however, by i.p. injections of large amounts of either non-radioactive methionine 30 min after intraocular labeling with [35S]methionine, or non-radioactive leucine given at the time of intraocular labeling. Whereas the former competes with the radioactive precursor during incorporation into brain proteins (after most of the retinal labeling has already been achieved), the latter competes at the earlier stage of access to the brain. Both methods reduced background labeling by more than 60%, thereby allowing for unambiguous identification of axonally transported proteins. The pattern of rapidly transported proteins was found to be strikingly different between neonates and mature animals, including marked changes in an identified 'growth-associated protein' (50 kDa, pI 4.8).

Amino Acids↗
PubMed1991

Selective expression of Jun proteins following axotomy and axonal transport block in peripheral nerves in the rat: evidence for a role in the regeneration process.

Expression of the protein products of the immediate-early genes (IEGs), members of the fos, jun and krox families (Jun, Fos, and Krox, resp.) was investigated in the spinal cord and sensory ganglia (DRG) of normal rats; and following transection of, block of axonal transport in, or electrical stimulation of their peripheral axons. The nuclei of many moto- and DRG neurons showed a faint basal immunoreactivity (IR) for Jun proteins, but not for Fos or Krox proteins. There was a strong and selective induction of Jun-IR in moto- and DRG neurons after peripheral nerve transection or crush, or colchicine- or vinblastine-induced block of axonal transport. The Jun-IR induced by nerve transection disappeared after nerve regeneration. In contrast, Jun, Fos and Krox proteins were all induced transynaptically in spinal dorsal horn neurons following electrical stimulation of the C-fibers in the afferent nerves. Thus in differentiated neurons in vivo these IEG proteins can be expressed either independently or concomitantly depending on the type of stimulus.

Animals↗
PubMed1980

Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport.

Intraocular pressure (IOP) elevations lasting from 2 to 42 days were produced in 13 primate eyes by anterior chamber injections of autologous, fixed red blood cells. The retina, optic nerve head, and optic nerves were studied by electron microscopy, and ganglion cell rapid axonal transport was examined after IOP elevations for various durations. Transport of axonal material was blocked at the scleral lamina cribrosa by IOP elevations to 50 mm Hg. With IOP elevation for less than 1 week, return to normal IOP restored normal transport in some axons. However, in other axons IOP elevation for less than 1 week intiated ganglion cell degeneration. The process of cellular death involved a rapid ascending degeneration from nerve head to brain, followed 3 to 4 weeks later by descending degeneration of the ganglion cell body and its attached axon. Axons of the superior and inferior optic nerve head and nerve seem to be damaged more extensively than those in the nasal and temporal optic nerve. Two to four days after IOP elevation, axons of the superficial optic nerve head were swollen with accumulating axonal material, leading to histologic disk edema. In those eyes with IOP elevation longer than 1 week, the loss of anterior disk nerve fibers combined with posterior and lateral movement of the lamina cribrosa lead to an increase in optic disk cupping. Astrocytes and capillaries of the optic nerve head seem to tolerate elevated IOP well and were relatively spared.

Animals↗
PubMed1994

In vivo neuronal synthesis and axonal transport of Kunitz protease inhibitor (KPI)-containing forms of the amyloid precursor protein.

We have shown previously that the amyloid precursor protein (APP) is synthesized in retinal ganglion cells and is rapidly transported down the axons, and that different molecular weight forms of the precursor have different developmental time courses. Some APP isoforms contain a Kunitz protease inhibitor (KPI) domain, and APP that lacks the KPI domain is considered the predominant isoform in neurons. We now show that, among the various rapidly transported APPs, a 140-kDa isoform contains the KPI domain. This APP isoform is highly expressed in rapidly growing retinal axons, and it is also prominent in adult axon endings. This 140-kDa KPI-containing APP is highly sulfated compared with other axonally transported isoforms. These results show that APP with the KPI domain is a prominent isoform synthesized in neurons in vivo, and they suggest that the regulation of protease activity may be an important factor during the establishment of neuronal connections.

Amyloid beta-Protein Precursor↗