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PubMed1983

Pressure-induced fast axonal transport abnormalities and the anatomy at the lamina cribrosa in primate eyes.

In ten owl monkey eyes (Aotus trivirgatus) the location of pressure-induced (perfusion pressure 35 mmHg) axonal transport abnormalities was determined by the examination of serial step cross-section tissue radio autographs from the optic nerve head. The degree of the local transport interruption did not correlate with the fiber bundle cross-section area, the shape of the laminar pores or the density of the inter-bundle septa in that region.

Animals↗
PubMed2006

Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin.

Peripherin is a type III neuronal intermediate filament detected in motor neuron inclusions of amyotrophic lateral sclerosis (ALS) patients. We previously reported that overexpression of peripherin provokes late-onset motor neuron dysfunction in transgenic mice. Here, we show that peripherin overexpression slows down axonal transport of neurofilament (NF) proteins, and that the transport defect precedes by several months the appearance of axonal spheroids in adult mice. Defective NF transport by peripherin up-regulation was further confirmed with dorsal root ganglia (DRG) neurons cultured from peripherin transgenic embryos. Immunofluorescence microscopy and western blotting revealed that excess peripherin provokes reduction in levels of hyperphosphorylated NF-H species in DRG neurites. Similarly the transport of a green fluorescent protein (GFP)-tagged NF-M, delivered by means of a lentiviral construct, was impaired in DRG neurites overexpressing peripherin. These results demonstrate that peripherin overexpression can cause defective transport of type IV NF proteins, a phenomenon that may account for the progressive formation of ALS-like spheroids in axons.

Amyotrophic Lateral Sclerosis↗
PubMed1980

Corticocortical connections of the cat sensory areas studied by means of retrograde axonal transport of horseradish peroxidase.

Afferent association connections to each functional cortex, i.e., the auditory, sensorimotor, visual, and "association" cortex, were investigated in the cat with the method of retrograde axonal transport of horseradish peroxidase (HRP). After injections of HRP in various parts of the cerebral cortex, a large number of labeled cells were found within the same functional areas, while a small number of cells were labeled in other cortical areas. This demonstrates that small parts within the functionally uniform cortical area are strongly interconnected by means of short association fibers. Labeled cells were found both in the cortex of the gyral surfaces and sulcal walls. Corticocortical neurons in the walls of some sulci were also shown to send their axons to various sensory areas. Cells of the origin of association fibers were mostly pyramidal in shape, occurring mainly in layer III of the various cortical areas (about 70% of the total number). Following injections of HRP suspension into the visual cortex, however, the majority of labeled cells (82%) were found in layers V and VI of the Clare-Bishop area, some of them were polygonal in shape. Somal diameters of the labeled cells were 15.8-17.2 micron (mean) +/- 2.5-3.0 (SD).

Afferent Pathways↗
PubMed1990

Retrograde axonal transport of an exogenous enzyme covalently linked to B-IIb fragment of tetanus toxin.

Attempt to replace enzymes in a number of fatal lysosomal storage disease involving the central nervous system have as yet been unsuccessful owing to the impermeability of the blood/brain barrier to macromolecules. In order to treat storage disease due to enzyme deficiencies, we investigated the feasibility of transporting an enzyme into the central nervous system without crossing the blood/brain barrier. Using the B-IIb fragment of tetanus toxin (because it is involved in recognition by the nerve-cell endings), retrograde axonal transport toward the spinal cord and trans-synaptic movement, and glucose oxidase as a marker, we demonstrated that a non-toxic enzyme-vector conjugate was taken up by axon terminals. After injection into the gastrocnemius muscle, the B-IIb-glucose oxidase conjugate was detected, both histologically and electrochemically, distally to a ligature on the sciatic nerve. Thus the B-IIb fragment could serve as a vector for glucose oxidase transport into the central nervous system. It was also verified that the transported enzyme retained its activity. Transport of this 150 kDa molecule by fragment B-IIb of tetanus toxin suggests that other enzymes of a lesser molecular mass may also be transported.

Animals↗
PubMed1988

Changes in fast axonally transported proteins in the regenerating rabbit vagus nerve.

Regeneration was induced in rabbit vagus nerves by a crush injury. Fourteen and 50 days later [35S]methionine-radiolabelled, fast axonally transported proteins were separated by one- and two-dimensional electrophoresis. Quantitative densitometric analysis of fluorographs from one-dimensional separations showed increases in the radiolabelling of fast transported proteins of 45 and 20 kDa, and a decrease in the radiolabelling of a 26 kDa protein 14 days after crush injury, which were confirmed by two-dimensional separations. These increases were maintained at 50 days post-crush. The proteins have similar molecular weights and isoelectric points to two growth-associated proteins known to have important roles in growth and regeneration.

Animals↗
PubMed1987

Increased axonal transport in peripheral nerves of thiamine-deficient rats.

Thiamine deficiency has been implicated as a significant contributing factor in the development of peripheral neuropathies in chronic alcoholic patients. We hypothesized that thiamine deficiency may lead to an alteration in axonal transport because it has been associated with "dying-back" neuropathies and its importance in neural tissue has been demonstrated with antimetabolites. To test this possibility rats were made thiamine-deficient by feeding a liquid diet lacking thiamine. Control rats were pair-fed a complete liquid diet. The deficiency developed after 3 to 4 weeks and was evidenced by anorexia, weight-loss, and a significant increase in the erythrocyte transketolase activity ratio. Also, the sural nerve conduction velocity was found to be significantly reduced in these animals (18.74 m/s) relative to that of pair-fed control rats (31.99 m/s). In vitro transport experiments utilizing dorsal root ganglia-sciatic nerve preparations indicated that twice as much [35S]methionine-labeled protein accumulated at a ligation by fast transport in the thiamine-deficient rats as in nerves of their pair-fed controls. There was no difference in the level of incorporation of radioactive precursor into the dorsal root ganglia. The increase in transport suggests that thiamine deficiency per se has no detrimental effects on the transport machinery and process, but may indicate extensive regenerative activity in the distal portions of these axons.

Animals↗
PubMed1980

Axonal transport of proteins. A new view using in vivo covalent labeling.

The injection of [2,3-3H]N-succinimidyl propionate ([3H]N-SP) into the rat sciatic nerve was used to covalently label both intra- and extra-axonal proteins. While extra-axonal proteins (e.g., myelin proteins) remained in the injection site, the intra-axonal proteins were transported in both the anterograde and retrograde directions. The mobile labeled proteins appeared to move by normal axonal transport processes because: (a) autoradiographic studies showed that they were localized exclusively within the axon at considerable distances from the injection site, (b) specific and identifiable proteins (by SDS gel electrophoresis) moved at expected rates in the anterograde direction, and (c) an entirely different profile of proteins moved in the anterograde vs. retrograde direction. This novel experimental approach to axonal transport, which is independent of de novo protein synthesis, provided a unique view of slow anterograde transport, and particularly of retrograde transport of endogenous proteins. A large quantity of a 68,000 mol wt proteins, moving at approximately 3-6 mm/day, dominated the retograde transport profile. [3H]N-SP, therefore, represents a new and unique "vital stain" which may find many applications in cell biology.

Animals↗
PubMed2004

What is the importance of multivesicular bodies in retrograde axonal transport in vivo?

Neurons with long axons have a unique problem in generating signaling cascades that are able to reach the nucleus after receptor activation by neurotrophins at the nerve terminal. The straightforward concept of receptor binding and local generation of 2nd second messenger cascades is too simplistic. In this review we will outline a mechanism that would enable the complex signals generated at the nerve terminal to be conveyed intact to the cell body. There are three different sites in the neuron where 2nd messenger proteins can interact with the signaling complex and be activated. Signaling cascades are initiated both at the nerve terminal and at the cell body when 2nd messengers are recruited to the plasma membrane by activated receptors. After receptor-mediated endocytosis, 2nd messenger molecules continue to be recruited to the internalized vesicle; however, the mix of proteins differs in the nerve terminal and in the cell body. At the nerve terminal the activated pathways result in the formation of the neurotrophin signaling endosome, which includes molecules to be retrogradely transported to the cell body. When the retrograde neurotrophin signaling endosome reaches the cell body, it can recruit additional 2nd messenger molecules to finally generate the unique signal derived from the nerve terminal. We propose that the multivesicular body observed in vivo functions as an endosome carrier vehicle or retrosome. This retrosome enables the mix of signaling molecules recruited at the terminal to be transported intact to the cell body. This will allow the cell body to receive a snapshot of the events occurring at the nerve terminal at the time the retrosome is formed.

Animals↗
PubMed1996

Effects of exogenous triiodothyronine on fast axonal transport during tadpole metamorphosis.

Bullfrog tadpoles at metamorphic stages V, X and XVIII were immersed in 25 nM triiodothyronine (T3) to assess whether the 4-5 fold increase in fast axonal transport (FAxT) previously observed during this span of spontaneous metamorphosis (1) could be mimicked by precocious application of thyroid hormone. The trend initially observed was for T3 to stimulated [35S]methionine incorporation into lumbar DRG and inhibit incorporation in tail DRG. Both effects, however, appeared to be exerted primarily on satellite cells rather than neurons since most of the T3-induced changes in DRG were of a similar magnitude to those in the respective nerve trunks. Findings consistent with this observation resulted from use of the retrogradely transported lectin, ricin120, to determine the proportion of DRG incorporation occurring in neurons. When incorporation of [35S]methionine in lumbar DRG neurons was examined, T3 had no stimulatory effect at any of the metamorphic stages examined. When FAxT was assessed as [35S]protein accumulating proximal to a nerve trunk ligature, and expressed as a percentage of newly-synthesized protein in lumbar DRG neurons, no stimulatory effect of T3 was detected. The question remains whether the changes in FAxT in peripheral neurons observed during spontaneous metamorphosis may be induced by circulating hormones other than T3 or are secondary to changes in the target tissues.

Animals↗
PubMed2004

Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model.

We tested the hypothesis that microtubule (MT)-binding drugs could be therapeutically beneficial in tauopathies by functionally substituting for the MT-binding protein tau, which is sequestered into inclusions of human tauopathies and transgenic mouse models thereof. Transgenic mice were treated for 12 weeks with weekly i.p. injections of 10 or 25 mg/m(2) paclitaxel (Paxceed). Both doses restored fast axonal transport in spinal axons, wherein MT numbers and stable (detyrosinated) tubulins were increased, compared with sham treatment, and only Paxceed ameliorated motor impairments in tau transgenic mice. Thus, MT-stabilizing drugs could have therapeutic potential for treating neurodegenerative tauopathies by offsetting losses of tau function that result from the sequestration of this MT-stabilizing protein into filamentous inclusions.

Animals↗
PubMed1982

Slow axonal transport of the molecular forms of butyrylcholinesterase in a peripheral nerve.

Butyrylcholinesterase was found in chick sciatic nerve in four main molecular forms--G1, G2, G4 and A12--distinguishable by thier sedimentation coefficients in sucrose gradients (4.2S, 6.4S, 11.3S and 19S, respectively). Axonal transport of butyrylcholinesterase was studied by measuring the accumulation of its molecular forms on each side of a transected sciatic nerve. Twenty-four hours after transection, butyrylcholinesterase activity had risen by about 32% at the extremity of the proximal stump, and by 20% at the extremity of the distal stump. Proximal accumulation was due to a two-fold rise in G4 activity and to a six-fold rise in A12 activity, whereas distal accumulation was exclusively due to a 50% increase in G4 activity, accompanied by the complete loss of A12. The activities of G1 and G2 remained stable in both directions. Under our experimental conditions, the accumulation of butyrylcholinesterase activity cannot be attributable to local protein synthesis, cross-contamination with accumulated acetylcholinesterase or the presence of plasma butyrylcholinesterase. Hence we conclude that all A12 butyrylcholinesterase molecules were carried in the anterograde direction, moving at 11.6 +/- 4.2 mm/day, and that probably some of the G4 molecules were slowly transported in both directions. These findings suggest that some of the butyrylcholinesterase is located in the axonal mitochondria and/or axolemma.

Animals↗
PubMed1978

ATP in cholinergic nerves:evidence for the axonal transport of a stable pool.

The ATP content of the cholinergic electromotor nerves of Torpedo marmorata has been measured. After freezing and thawing of pieces of nerve, their ATP content dropped rapidly to about 5% of that of pieces extracted immediately. The amount of ATP in nerves incubated in Torpedo Ringer remains at a high level over a long period. In nerves ligated for seven days there is no accumulation of total ATP above the ligature. If, however, the ligated nerves are frozen and thawed for 20 min before extraction, the residual ATP shows significant proximal accumulation at the ligature. This transport is not due to the accumulation of mitochondria at the ligature.Acetylcholine, measured in the same nerve extracts of nerve segments, is also axonally transported. The ATP which is resistant to hydrolysis is probably sequestered within a subcellular organelle. The possibility that its accumulation at ligatures may indicate movement of cholinergic synaptic vesicles which are known to contain ATP and acetylcholine is considered.

Acetylcholine↗
PubMed1977

Demonstration of bilateral claustro-cortical connections in the cat with the method of retrograde axonal transport of horseradish peroxidase.

The claustrum of the cat was studied to determine the extent of its projection to the cerebral cortex. Neurons in the bilateral dorsal claustrum are labeled by retrograde axonal transport of horseradish peroxidase (HRP) from injection sites of different neocortical areas with preponderance to the ipsilateral side. It is revealed that the dorsal claustrum projects to almost entire regions of the bilateral neocortex and that distribution of labeled neurons in the bilateral claustrum has topographical correspondence, rostro-caudal as well as dorso-ventral, with regard to the sites of injections in the neocortex. No neurons in the ventral claustrum are labeled.

Animals↗
PubMed1988

Serotonergic projections to the spinal cord but not those to the olfactory bulb also contain substance P. A combined immunocytochemical and autoradiographic study following retrograde axonal transport of [3H]serotonin labeled products.

Co-localization of substance P with serotonin in raphe projection neurons was studied by combining substance P immunocytochemistry and autoradiography following uptake and retrograde axonal transport of [3H]serotonin and/or its products from target areas. In this study, two central pathways in the rat were investigated: the serotonergic projections of the midbrain raphe to the olfactory bulb and those of the medullary raphe that innervate the thoracic spinal cord. Two hours after pargyline pretreatment, injections of 10(-4) M [3H]serotonin were made either into the olfactory bulb or into the spinal cord and respectively 24 or 60 h thereafter, rats were administered with colchicine. After a 24 h survival time, the paraformaldehyde fixed brains were investigated for substance P immunocytochemistry and then treated for light and electron microscopy autoradiography. Combining both methods, we can define on the same tissue sections at least three labeled neuronal populations: substance P immunolabeled neurons, radiolabeled neurons and doubly immuno-radiolabeled neurons. In the midbrain raphe cells as well as in the olfactory bulb nerve terminals, two kinds of labeled profiles were detected: substance P immunoreactive profiles and radiolabeled ones. The radiolabeled cell bodies of the midbrain raphe (403 counted cells) were never reactive to substance P antibodies. Moreover, they were distributed caudally to substance P stained perikarya. In contrast, in the medullary raphe, of the 336 radiolabeled cell bodies 162 were stained after substance P antibody treatment. They represent about 48% of the serotonin radiolabeled neurons projecting to the thoracic spinal cord, where a great number of varicosities were observed immunolabeled, radiolabeled and doubly immuno-radiolabeled in the dorsal horn. At the ultrastructural level, cell bodies and dendritic processes were also doubly labeled. Both labelings were observed over the cytoplasm and some organelles or perikarya. These observations provide a morphological basis to support the hypothesis that substance P can occur within some but not all serotonergic neurons and raise questions about the expression of this peptide in these systems as well as the modes of interaction of these transmitter molecules.

Animals↗
PubMed1979

Membrane glycolipids: regional synthesis and axonal transport in a single identified neuron of Aplysia californica.

Glycolipids moving along an identified axon Aplysia californica were synthesized and incorporated into intracytoplasmic membranes solely in the perikaryon: direct injection of tritiated sugar into the axon revealed no local synthesis or exchange. There was no indication for transfer into axoplasm from glia. Insertion of glycolipids into nascent membranes occurs coordinately with insertion of protein components in the cell body.

Animals↗
PubMed2003

Age-dependent changes in axonal transport and cellular distribution of Tau 1 in the rat basal forebrain neurons.

Basal forebrain (BF) cholinergic neurons are prone to degeneration due to age-dependent impairment of uptake and retrograde axonal transport of NGF. Modification and intracellular redistribution of cytoskeletal tau proteins could be responsible for this process. In this study we injected fluorogold (FG) into neocortex and hippocampus of young and aged rats. The number of neurons retrogradely labeled with FG in subdivisions of BF was significantly lower in aged rats than in young ones. We also characterized the distribution of Tau 1 in cellular compartments of BF and hippocampal neurons. Tau 1 immunostaining restricted to neuritic structures was observed in neurons of septo-hippocampal pathways in young rats. In contrast, aged rats displayed the presence of Tau 1 isoform mainly in the somatodendritic compartment of BF neurons. The findings demonstrate that in aged rats reduced retrograde labeling of BF neurons coincide with lower expression of cholinergic markers and is accompanied by altered cellular distribution of Tau 1.

Acetylcholine↗
PubMed1996

Type I brain hexokinase: axonal transport and membrane associations within central nervous system presynaptic terminals.

While studying the delivery of cytoplasmic proteins to the presynaptic terminals of CNS neurons, we discovered unique characteristics of one protein (p118) conveyed in slow component b (SCb) of axonal transport, the large group of proteins representing the cytoplasmic matrix. Alone among the SCb group, p118 coisolated with the synaptic junctional complex on biochemical fractionation of the radiolabeled synaptic regions. Purification and amino acid sequencing of this protein revealed it is most likely the guinea pig form of type I (brain) hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1). Further biochemical treatments were consistent with this identity. The majority of type I brain hexokinase has been thought to be associated primarily with membranes, in particular the mitochondrial outer membrane. We found that the majority of type I hexokinase is transported toward the terminals at a rate at least 10 times slower than that exhibited by the maximal or average rate of mitochondria. This suggests that, in the axon, the enzyme exhibits transient or dynamic interactions with mitochondria that are moving more rapidly. It is not clear whether hexokinase binds exclusively to mitochondria, or also exhibits association with nonmitochondrial membranes. The unexpected enrichment of hexokinase during synaptic junctional complex purification may result from its strong association with the presynaptic membrane portion of the synapse.

Amino Acid Sequence↗
PubMed1984

Axonal transport of muscarinic receptors in vesicles containing noradrenaline and dopamine-beta-hydroxylase.

Presynaptic muscarinic receptors labeled with [3H]dexetimide and noradrenaline in dog splenic nerves accumulated proximally to a ligature at the same rate of axonal transport. After fractionation by differential centrifugation, specific [3H]quinuclidinyl benzilate or [3H]dexetimide binding revealed a distribution profile similar to that of dopamine-beta-hydroxylase and noradrenaline. Subfractionation by density gradient centrifugation showed two peaks of muscarinic receptors; the peak of density 1.17 contained noradrenaline and dopamine-beta-hydroxylase whereas that of density 1.14 was devoid of noradrenaline. Therefore the foregoing experiments provide evidence that presynaptic muscarinic receptors are transported in sympathetic nerves in synaptic vesicles which are similar to those containing noradrenaline and dopamine-beta-hydroxylase. This suggests a possible coexistence of receptor and neurotransmitter in the same vesicle.

Animals↗