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PubMed1997

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport.

A sensitive immunohistochemical technique was used, along with highly specific affinity-purified antibodies to brain-derived neurotrophic factor (BDNF), to generate a detailed mapping of BDNF immunoreactivity (BDNF-ir) throughout the adult rat CNS. A parallel analysis of sites of BDNF synthesis was performed with in situ hybridization techniques using a cRNA probe to the exon encoding mature rat BDNF protein. These combined data revealed (1) groups of cell bodies containing diffuse BDNF-ir throughout the CNS that were strongly correlated with fields of cells containing BDNF mRNA; (2) varying degrees of BDNF-ir outside of cell bodies, in what appeared to be fibers and/or terminals; and (3) many regions containing extremely heavy BDNF-immunoreactive fiber/terminal labeling that lacked BDNF mRNA (e.g., medial habenula, central nucleus of the amygdala, bed nucleus of stria terminalis, lateral septum, and spinal cord). The latter observation suggested that in these regions BDNF was derived from anterograde axonal transport by afferent systems. In the two cases in which this hypothesis was tested by the elimination of select afferents, BDNF immunostaining was completely eliminated. These data, along with the observation that BDNF-ir was rarely found within dendrites or fibers en passage, suggest that BDNF protein produced in adult CNS neurons is polarized primarily along axonal processes and is preferentially stored in terminals within the innervation target.

Animals↗
PubMed1991

Nerve conduction velocity and axonal transport of 6-phosphofructokinase activity in galactose-fed rats.

This study examined sciatic motor nerve conduction velocity (MNCV) and the accumulation of 6-phosphofructokinase (PFK) activity proximal and distal to a sciatic nerve ligature in rats fed a diet containing 20% galactose for 4 weeks. MNCV was reduced in the galactose-fed rats to 94% of controls, (P less than 0.05) but PFK activity accumulations were not different from those in controls. Daily administration of the aldose reductase inhibitor ponalrestat throughout the study to another group of galactose-fed rats prevented dulcitol accumulation, myo-inositol depletion and increased water content of the sciatic nerve seen in galactose-fed rats. This effective aldose reductase inhibition also prevented the reduced MNCV and had no effect on accumulations of PFK activity. These data support earlier work suggesting that deficits in the axonal transport of PFK activity in diabetic rats are unrelated to either exaggerated flux through the polyol pathway, polyol accumulation or ischemic hypoxia and indicate the possible need for the elucidation of other pathogenic mechanisms which may contribute to the development of diabetic neuropathy.

Aldehyde Reductase↗
PubMed1980

Retrograde axonal transport following injection of [3H]-serotonin into the olfactory bulb. II. Radioautographic study.

Radioautography was used to study the intraneuronal distribution of [3H]-serotonin (5-HT) and/or its derivatives selectively taken up by the olfactory bulb (OB) serotonergic terminals and subsequently transported to their parent cell bodies in the midbrain raphe nuclei. This was done 24 h after injection of [3H]5-HT into the main OB of rats either pretreated or not with monoamine oxidase (MAO) inhibitor. A prior mechanical obstruction of the rostral ventricular cavities prevented diffusion of the tracer towards cerebrospinal fluid. Heavily labelled nerve cell bodies were found mainly in the ipsilateral raphe dorsalis nucleus (RDN) and to a lesser extent in the raphe centralis nucleus. The radioautographic reaction often extended to dendritic processes while sparing the nucleus. A diffuse reaction was also observed but limited to the raphe area. The supraependymal 5-HT fibers were found to be free of labelling. Neither local destruction of catecholaminergic terminals with 6-OHDA, nor absence of MAO inhibition, impaired this radioautographic pattern, while destruction of serotonergic terminals with 5,6-dihydroxytryptamine in OB resulted in the disappearance of labelled axonal varicosities and neurons in the OB and the RDN respectively. At the electron microscopy level, labelled cell bodies in the RDN were medium-sized (12-15 micrometers). Silver grains were localized mainly on mitochondria and, to a lesser extent, on lysosomes and endoplasmic reticulum but spared the nucleus and the nucleolus. Silver grains were also found near the nuclear membrane and outside the neuronal membrane. The observation of heavy metal impregnated thick sections confirmed the preferential localization of silver grains on mitochondria with or without inhibition of MAO. These results could account for the subcellular compartments involved in the retrograde axonal transport of [3H]5-HT and its subsequent degradation and/or dendritic release.

Animals↗
PubMed1975

Localization of masticatory motoneurons in the cat and rat by means of retrograde axonal transport of horseradish peroxidase.

Topographical localization of monotoneurons supplying the masticatory muscles was investigated in the cat and rat, utilizing retrograde axonal transport of horseradish peroxidase. Following injection of horseradish peroxidase in each masticatory muscle, motoneurons labelled with peroxidase were seen to be aggregated into a cluster within the motor nucleus of the trigeminal nerve. Such clusters of peroxidase-motoneurons innervating each masticatory muscle were demarcated more sharply in kittens than in adult animals. The pattern of the nuclear representation of the masticatory muscles was found to be essentially the same in the cat and rat; it could be summarized as follows: The motor nucleus of the trigeminal nerve could be divided cytoarchitectonically into the dorsolateral and ventromedial divisions; the former was seen in almost the whole rostrocaudal extent of the nucleus, while the latter was localized at the levels of caudal two thirds of the nucleus. In the dorsolateral division, the temporal muscle was represented dorsally and dorsomedially, the masseter muscle ventrolaterally, and the pterygoid muscles ventromedially. In the ventromedial division, the anterior digastric muscle was represented dorsomedially, and the mylohyoid muscle ventrolaterally. It was also confirmed that the motoneurons supplying the posterior digastric muscle were localized in the accessory facial nucleus.

Animals↗
PubMed1994

Characterization of the KLP68D kinesin-like protein in Drosophila: possible roles in axonal transport.

This paper describes the molecular and biochemical properties of KLP68D, a new kinesin-like motor protein in Drosophila melanogaster. Sequence analysis of a full-length cDNA encoding KLP68D demonstrates that this protein has a domain that shares significant sequence identity with the entire 340-amin acid kinesin heavy chain motor domain. Sequences extending beyond the motor domain predict a region of alpha-helical coiled-coil followed by a globular "tail" region; there is significant sequence similarity between the alpha-helical coiled-coil region of the KLP68D protein and similar regions of the KIF3 protein of mouse and the KRP85 protein of sea urchin. This finding suggests that all three proteins may be members of the same family, and that they all perform related functions. KLP68D protein produced in Escherichia coli is, like kinesin itself, a plus-end directed microtubule motor. In situ hybridization analysis of KLP68D RNA in Drosophila embryos indicates that the KLP68D gene is expressed primarily in the central nervous system and in a subset of the peripheral nervous system during embryogenesis. Thus, KLP68D may be used for anterograde axonal transport and could conceivably move cargoes in fly neurons different than those moved by kinesin heavy chain or other plus-end directed motors.

Amino Acid Sequence↗
PubMed1991

The role of axonal transport in neurodegenerative disease spread: a meta-analysis of experimental and clinical poliomyelitis compares with amyotrophic lateral sclerosis.

ALS symptom spread results from local spread of the neuronal degeneration because contiguous areas are more quickly involved than non-contiguous areas. Local spread to contiguous areas of motor neuron dysfunction is faster at the brainstem, cervical and lumbar regions than spread to non-contiguous areas. The time for caudal-rostral symptomatic spread of ALS to involve a distant region is a function of the distance of that region from the site of onset. The time for spread to the bulbar region is shorter following arm onset than leg onset. Spread to non-contiguous areas is faster within the spinal cord than from the spinal cord to the bulbar region. These kinetics are consistent with axonal transport of the etiological agent in a manner similar to spread of poliovirus in poliomyelitis patients. Spread from the bulbar region to the spinal cord, on the other hand, occurs faster than symptom spread from the limb region to the bulbar region in limb onset patients. This rapid limb involvement following bulbar onset is more dramatic in males compared with females. Females with leg onset, on the other hand, show more rapid involvement of the opposite leg, either arm or bulbar structures than males. Gender effects may determine the course of ALS depending on the original site of onset.

Amyotrophic Lateral Sclerosis↗
PubMed1975

Retrograde axonal transport of horseradish peroxidase in peripheral autonomic nerves.

An exogeneous marker protein, horseradish peroxidase (HRP) was used to race peripheral autonomic pathways in adult guinea pigs and cats. Small doses of HRP were injected into various organs and after a brief survival period, HRP activity appeared in the perikarya of autonomic neurons that supplied each injection site. After injection of HRP into the anterior chamber of the eye, reaction product was detected in the postganglionic sympathetic neurons of the superior cervical sympathetic ganglion. In another experiment, HRP reaction product was found in the cell bodies of the preganglionic sympathetic neurons that supply the adrenal medulla. These were located in the lateral gray column of the spinal cord at T6 and T7 segmental levels. Reaction product appeared in intramural postganglionic parasympathetic neurons close to an injection site in the wall of the urinary bladder and in a similiar situation in Meissner's ganglia of the ileum. Following injection into the walls of the stomach and ileum, HRP labelled cells were detected in the nodose ganglion of the vagus and in preganglionic parasympathetic neurons in the dorsal motor nucleus of this nerve. After injection into the subepicardial tissue of the heart, reaction product appeared in the stellate ganglion and also in an upper thoracic dorsal root ganglion. These data suggest that HRP is taken up by peripheral autonomic nerves of all types, and then undergoes rapid retrograde axonal transport to the perikaryon. It appears, therefore, that HRP may be useful in tracing both motor and sensory peripheral autonomic pathways.

Adrenal Medulla↗
PubMed1983

Axonal transport of glycerophospholipids in regenerating sciatic nerve of the rat during aging.

The effect of age upon the axoplasmic transport of glycerophospholipids has been studied using as a model the regenerating sciatic nerve of young (2-month-old), young adult (6-month-old), middle-aged (16-month-old), and aged (20-month-old) male rats. The right sciatic nerve was crushed 0.5 mm down the incisura ischiadica. Four and nine days after the lesion, a mixture of [2-3H] glycerol and [methyl-14C] choline was bilaterally injected into the spinal cord, at a level of the L4-L5 vertebrae. The animals were killed 18 hr after the isotope injection. Proximal and distal portions of crushed nerve and of contralateral sham-operated ones were dissected and consecutive 5-mm segments were subjected to lipid extraction and analysis. The findings of the present study are summarized as follows: (1) The accumulation of labeled lipid material axonally transported four days after nerve injury was mainly located at the crush site in young, young adult, middle-aged, and aged rats. The accumulation of both 3H-glycerolipids and 14C-choline phospholipids in postcrush segments was markedly higher for young and young adult than for aged rats, four and nine days after crush; (2) the average rate of axonal regeneration, determined between days 4 and 9 following crush injury was 3.6 and 4.2 mm/day for 2-month-old and 6-month-old rats, respectively; it decreased to the value of 2.5 mm/day for 16-20-month-old rats.

Aging↗
PubMed2002

Fast axonal transport misregulation and Alzheimer's disease.

Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer's Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.

Alzheimer Disease↗
PubMed1995

Visualization of beta-adrenoceptor binding sites on human inferior vagal ganglia and their axonal transport along the rat vagus nerve.

DESIGN: Because of uncertainties regarding the complete antihypertensive mechanism of action of beta-adrenoceptor antagonists, the present study determined whether vagal afferent neurons of humans and rats possess beta-adrenoceptors. Such a location would provide an appropriate target for beta-blockers to modulate neurotransmission of barosensitive neurons, thereby affecting blood pressure. Therefore, in vitro receptor autoradiography of high-affinity beta-adrenoceptor binding sites was performed on slices of human and rat inferior vagal (nodose) ganglia with [125I]-pindolol. METHODS: Slide-mounted sections of human and rat inferior vagal ganglia were incubated with [125I]-pindolol in the absence or presence of propranolol (10 mumol/l) to define non-specific binding, atenolol (10 mumol/l) to inhibit binding to beta 1-adrenoceptors, or ICI 118551 (3 nmol/l) to inhibit binding to beta 2-adrenoceptors. Unilateral vagal ligation was also performed in the rat to study whether beta-adrenoceptors are subject to axonal transport along the vagus nerve. RESULTS: [125I]-pindolol bound with > 90% specific binding to sections both of human and of rat inferior vagal ganglia. Specific binding occurred over both neuronal perikarya and nerve fibres. In both species the beta 2-adrenoceptor subtype appeared to predominate, as defined by the differential ability of ICI 118551 (beta 2) and atenolol (beta 1) to inhibit the binding of [125I]-pindolol. Furthermore, unilateral vagal ligation in the rat caused an accumulation of specific binding adjacent to the ligature sites. CONCLUSIONS: We conclude that human and rat vagal afferent (and efferent) neurons possess beta-adrenoceptors that potentially could explain the mechanism of action of beta-adrenoceptor antagonists in the therapy of hypertension.

Animals↗
PubMed1998

Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: evidence for increased synthesis and anterograde axonal transport.

Cellular localization and tissue levels of BDNF protein were studied using immunocytochemistry and enzyme immunoassay, respectively, in the cortex and striatum at different reperfusion times (0-24 h) after 2 h of unilateral middle cerebral artery occlusion (MCAO) in rats. The distribution of neuronal injury was analyzed in NeuN-, cresyl violet-, and Fluoro-Jade-stained sections. At 2 h postischemia, but not at later time points, there was a several-fold increase of the number of BDNF-immunoreactive (-ir) cells in the ipsilateral cingulate and frontal cortices outside the damaged area. Animals with cortical injury showed loss of BDNF-ir fibers in the striatum at 2-24 h, whereas rats with cell damage confined to the striatum exhibited no such change. At 2-16 h, strongly BDNF-ir fibers were observed along the myelinated fascicles medially in the striatum, in the anterior commissure, and in the corpus callosum ipsilateral to the MCAO. BDNF protein levels were increased (by 133-213%) at 2 h in the cingulate and frontal cortices and decreased (by 40%) at 24 h in the striatum. These findings show that the increased expression of BDNF mRNA in cortical neurons previously demonstrated after transient focal ischemia is accompanied by elevated levels of BDNF protein. The rapid decline of BDNF protein levels suggests a pronounced release or anterograde axonal transport in the postischemic phase. The reduction of BDNF protein in the striatum of animals with cortical damage provides further evidence for anterograde transport, which is also supported by the accumulation of BDNF protein in several preterminal fiber systems. The changes of BDNF protein after focal ischemia could play a role for survival and plasticity of cortical and striatal neurons.

Animals↗
PubMed2001

Calcium/calmodulin-dependent protein kinase IIalpha in optic axons moves with slow axonal transport and undergoes posttranslational modification.

In neurons, the mRNA for calcium/calmodulin-dependent protein kinase II alpha (CKIIalpha) is known to be targeted to dendrites-where the enzyme is synthesized and supports postsynaptic functions. We are interested in knowing how neuronal proteins enter axons from the nerve cell body, and the mechanism for protein transport to terminals. Because CKIIalpha immunofluorescence can be demonstrated in over 80% of retinal ganglion cells, we asked whether this regulatory protein is being transported into optic axons. Using Sprague-Dawley rats, [(35)S] methionine was injected into the vitreous humor of the eye. Four days later, the optic nerves, tracts, lateral geniculate ganglia, and superior colliculi were removed and processed for 2D-PAGE and Western blotting. Radiolabeled CKIIalpha appears to move with slow component b (SCb) of axonal transport, as is the case in rodent sciatic motor neurons. In addition, the radiolabeled CKIIalpha isoform that enters the optic nerve is found to be 4 kDa heavier (in SDS-PAGE molecular mass) than the isoform in the optic tract, superior colliculus, and lateral geniculate nucleus. This reduction is likely the result of dephosphorylation, which is a mechanism used to regulate the enzyme's activity.

Animals↗
PubMed1983

Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an aldose reductase inhibitor in streptozotocin-diabetic rats.

The effects of orally-administered myo-inositol have been compared with those of an aldose reductase inhibitor on acute neurological defects in experimentally diabetic rats. Three groups of streptozotocin-treated diabetic rats (50 mg/kg, IP) together with three groups of age-matched controls (saline, IP) were compared. One pair of groups (control and diabetic) were untreated for 3 weeks, another pair of groups received daily oral myo-inositol (667 mg/kg) and the third pair received an aldose reductase inhibitor (ICI 105 552; 50 mg . kg-1, day-1, orally). The untreated diabetic group showed statistically significant deficits in accumulation, proximal to 24 h sciatic nerve constrictions, of choline acetyltransferase activity by comparison with untreated controls (2.8 +/- 0.4 versus 5.1 +/- 0.4 nmol acetylcholine . h-1 . nerve-1; p less than 0.001). The untreated diabetic rats also showed a fall in motor nerve conduction velocity of 6.2 +/- 0.7 m/s which was statistically significant (p less than 0.001). Treatment of the diabetic group with myo-inositol prevented the development of both defects of axonal transport and conduction velocity; both measurements were similar to those of the myo-inositol treated control rats. Likewise the diabetic rats which received aldose reductase inhibitor showed prevention of both defects. Nerves from untreated diabetic rats showed marked sorbitol accumulation and a statistically significant reduction in myo-inositol content by comparison with the untreated controls (sorbitol, 1.56 +/- 0.22 versus 0.8 +/- 0.01 and myo-inositol, 1.47 +/- 0.10 versus 2.3 +/- 0.10 nmol/mg; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗