Nogo-66 receptor antagonist peptide (NEP1-40) administration promotes functional recovery and axonal growth after lateral funiculus injury in the adult rat.

Objective: The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST).

Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury.

The growth of injured axons in the adult mammalian CNS is limited after injury. Three myelin proteins, Nogo, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), bind to the Nogo-66 receptor (NgR) and inhibit axonal growth in vitro. Transgenic or viral blockade of NgR function allows axonal sprouting in vivo.

A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin.

The Nogo66 receptor (NgR1) is a neuronal, leucine-rich repeat (LRR) protein that binds three central nervous system (CNS) myelin proteins, Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein, and mediates their inhibitory effects on neurite growth. Although the LRR domains on NgR1 are necessary for binding to the myelin proteins, the exact epitope(s) involved in ligand binding is unclear. Here we report the generation and detailed characterization of an anti-NgR1 monoclonal antibody, 7E11.

Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein.

In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways.

Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation.

The data presented here demonstrate that sympathetic neurons have the potential to activate two alternative caspase-dependent pathways either of which is capable of mediating death induced by NGF deprivation and that these neurons have the potential to switch from one pathway to the other. The presence of these two alternative pathways to trophic factor deprivation-induced death may have implications for ensuring the correct development of the nervous system. In wild-type neurons, a caspase-2-dependent pathway is required for death, and a caspase-9-dependent pathway appears to be suppressed by endogenous inhibitors of apoptosis proteins (IAPs).

beta-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation.

beta-Amyloid (A beta) has been strongly implicated in the pathophysiology of Alzheimer's disease (AD), but the means by which the aggregated form of this molecule induces neuronal death have not been fully defined. Here, we examine the role of the c-Jun N-terminal kinases (JNKs) and of their substrate, c-Jun, in the death of cultured neuronal PC12 cells and sympathetic neurons evoked by exposure to aggregated A beta. The activities of JNK family members increased in neuronal PC12 cells within 2 h of A beta treatment and reached 3--4-fold elevation by 6 h.

Caspase-2 mediates neuronal cell death induced by beta-amyloid.

beta-amyloid (Abeta) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Abeta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Abeta induces death by oxidative stress, possibly through the generation of peroxynitrite from superoxide and nitric oxide.

BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy fiber neurons.

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF during mossy fiber synaptogenesis. To determine whether neurotrophins contribute to the development of cerebellar afferent axons, we characterized the effects of neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro.

Collapsin-1/semaphorin-III/D is regulated developmentally in Purkinje cells and collapses pontocerebellar mossy fiber neuronal growth cones.

Most axons in the CNS innervate specific subregions or layers of their target regions and form contacts with specific types of target neurons, but the molecular basis of this process is not well understood. To determine whether collapsin-1/semaphorin-III/D, a molecule known to repel specific axons, might guide afferent axons within their cerebellar targets, we characterized its expression by in situ hybridization and observed its effects on mossy and climbing fiber extension and growth cone size in vitro. In newborn mice sema-D is expressed by cerebellar Purkinje cells in parasagittal bands located medially and in some cells of the cerebellar nuclei.

Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2.

Approximately half of the retinal ganglion cells (RGCs) present in the rodent retina at birth normally die during early development. Overexpression of the photo-oncogene bcl-2 recently has been shown to rescue some neuronal populations from natural cell death and from degeneration induced by axotomy of nerves within the peripheral nervous system. Here we study in vivo the role of the overexpression of bcl-2 in the natural cell death of RGCs and in the degenerative process induced in these cells by transection of the optic nerve.

A developmentally regulated nerve growth factor-induced gene, VGF, is expressed in geniculocortical afferents during synaptogenesis.

The expression of the nerve growth factor-inducible gene VGF has been examined by in situ hybridization. Western blot and immunohistochemical studies in the developing and adult rat central nervous system, with particular emphasis on the visual system. Both the messenger RNA and the protein are particularly abundant in the developing dorsal lateral geniculate nucleus, appearing, respectively, at embryonal day 16 and 18.

Nerve growth factor reduces apoptosis of axotomized retinal ganglion cells in the neonatal rat.

It has recently been reported that the degeneration of retinal ganglion cells induced by transection of the optic nerve in the neonatal rat is due to an active process of apoptosis, as opposed to passive necrosis. Here we tested whether the administration of the trophic factor nerve growth factor could prevent the apoptotic death of the axotomized cells. We administered nerve growth factor by two intraocular injections, one immediately after the lesion and the second 12 h later.

Apoptotic cell death induced by optic nerve lesion in the neonatal rat.

Cell death can be ascribed to one of two distinct modes of degeneration: apoptosis (programmed or active cell death) or necrosis (passive degeneration). While apoptosis is generally assumed to occur in physiological conditions such as normal development or tissue turnover, necrotic cell degeneration is induced in pathological situations. Here we report that also in a pathological situation, such as after axotomy in the CNS, apoptotic type of cell death comes into play: following intracranial transection of the optic nerve in the neonatal rat in vivo, retinal ganglion cells undergo an active, apoptotic cell death.

Role of the target in synapse elimination: studies in cerebellum of developing lurcher mutants and adult chimeric mice.

As the mature nervous system is sculpted out of its embryonic anlage, regressive events are a surprisingly common feature. As one example, the establishment of adult innervation in the CNS and PNS often involves a massive withdrawal of previously formed functional synapses. In the cerebellum, the one-to-one relationship of inferior olivary climbing fibers to Purkinje cells is preceded by a transient stage in which each Purkinje cell is multiply innervated.

Involvement of the N-methyl D-aspartate (NMDA) receptor in synapse elimination during cerebellar development.

In many instances, the establishment of highly specific neuronal connections during development results from the rearrangement of axonal projections through the trimming of exuberant collaterals or the elimination of functional synapses or both. Although the involvement of the N-methyl D-aspartate (NMDA) subtype of the glutamate receptor has been demonstrated in the shaping of axonal arbors, its participation in the process of selective stabilization of synapses remains an open issue. In this study, the effects of chronic in vivo application of D,L-2-amino-5-phosphonovaleric acid (D,L-APV), a selective antagonist of the NMDA receptor, on the synapse elimination process that takes place in the developing cerebellum of the rat have been analyzed.

A positional marker for the dorsal embryonic retina is homologous to the high-affinity laminin receptor.

In a search for determinants of positional information in the embryonic eye, we isolated two monoclonal antibodies that label strongly the dorsal part of the undifferentiated embryonic retina in mammals, bird and cold-blooded vertebrates. In the chick, the optic tectum is labeled in a corresponding fashion, the ventral tectum more heavily than the dorsal tectum. Through biochemical and molecular analysis both antibodies were found to recognize a protein that has been cloned repeatedly, first in a screen with antibodies to the '68K-laminin receptor' (Wewer et al.

Influence of inferior olive on flexor reflex activity.

In Wistar rats we have studied the effect of inferior olive lesion or activation on the threshold of a flexor reflex elicited by a nociceptive stimulus applied to the hindpaw. When the inferior olive is lesioned by means of 3-acetylpyridine, the threshold value is significantly decreased. A recovery occurs in 3-4 weeks.

Inferior olive lesion induces long-lasting functional modification in the Purkinje cells.

In recent experiments Montarolo et al. (1982) have shown that reversible inferior oliver (IO) inactivation of up to 90 s induces a marked increase of the Purkinje cell (PC) simple spike (SS) frequency which lasts as long as the disappearance of the complex spikes (CS). The present work was aimed at studying how long this SS frequency increase lasts.