Axon guidance at the central nervous system midline

A key feature of the central nervous system of most higher organisms is their bilateral symmetry about the midline. The specialised cells that lie at the midline have an essential role in regulating the axon guidance decisions of both neurons that project axons across the midline and those that project on one side. The midline cells produce both attractive and repellent short- and long-range signals to guide axonal growth. The axons themselves express specific receptors that can be dynamically regulated in response to midline-derived signals. In this way, axons extend toward or away from the midline and those that do cross change their behaviour to respond to longitudinal signals on the contralateral side.     

Neurodegeneration changes in primary central nervous system neurons transfected with the Alzheimer-associated neuronal thread protein gene

The AD7c-NTP gene is over-expressed in brains with Alzheimer's disease (AD), and increased levels of the corresponding protein are detectable in cortical neurons, brain tissue extracts, cerebrospinal fluid, and urine beginning early in the course of AD neurodegeneration. In the present study, we utilized a novel method to transfect post-mitotic primary neuronal cell cultures, and demonstrated that over-expression of the AD7c-NTP gene causes cell death and neuritic sprouting, two prominent abnormalities associated with AD. These results provide further evidence that aberrantly increas-ed AD7c-NTP expression may have a role in AD-type neurodegeneration. In addition, we demonstrate that primary post-mitotic neurons can be efficiently transfected with conventional recombinant plasmid DNA to evaluate the effects of gene over-expression in relevant in vitro models. Received 31 January 2001; received after revision 31 March 2001; accepted 4 April 2001     

Local and target-derived actions of neurotrophins during peripheral nervous system development

Neurotrophic factors are present in limiting quantities, and neurons that obtain an adequate supply of the required neurotrophic factor survive whereas those that compete unsuccessfully die. Analysis of null mutant mice for neurotrophins and Trk receptors as well as in vivo experiments in ovo in the chick applying exogenous neurotrophins or neutralising antisera have significantly increased knowledge of the roles they play during development. This review focuses on recent advances in understanding the various roles of neurotrophins in dorsal root ganglion sensory neuron development at different times in embryonic development - an early local role for differentiation of the sensory precursor cells and a later survival-promoting target-derived role for the mature neurons. Neurotrophic factors are present in limiting quantities, and neurons that obtain an adequate supply of the required neurotrophic factor survive whereas those that compete unsuccessfully die. Analysis of null mutant mice for neurotrophins and Trk receptors as well as in vivo experiments in ovo in the chick applying exogenous neurotrophins or neutralising antisera have significantly increased knowledge of the roles they play during development. This review focuses on recent advances in understanding the various roles of neurotrophins in dorsal root ganglion sensory neuron development at different times in embryonic development - an early local role for differentiation of the sensory precursor cells and a later survival-promoting target-derived role for the mature neurons.     

Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons

Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated with H₂O₂ (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis and sprouting gene expression. H₂O₂ treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The H₂O₂-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin, and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection), and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast, hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration. Received 24 May 2000; received after revision 7 July 2000; accepted 27 July 2000     

Developmental and pathological angiogenesis in the central nervous system

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.     

Multitasking with neurotensin in the central nervous system

The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.Received 18 March 2005; received after revision 9 May 2005; accepted 23 May 2005     

Neuronal and glial markers of the central nervous system

Summary This brief review evaluates the expression of cell-specific markers on differentiated neural cells and, where necessary, on their developing precursors. Within these limitations only the commonly used markers are discussed and those deemed unequivocal are only briefly appraised.     

Cholesterol homeostasis and function in neurons of the central nervous system

Cholesterol is a multifaceted molecule. First, it serves as an essential membrane component, as a cofactor for signaling molecules and as a precursor for steroid hormones; second, its synthesis, intercellular transport and intracellular distribution present a logistic tour de force requiring hundreds of cellular components, and third, it plays a crucial role in major human diseases. Despite intense research on this molecule, its metabolism in the central nervous system and its role in neuronal development and function are not well understood. Here I summarize recent results and hypotheses about how neurons maintain their cholesterol level and how cholesterol influences the establishment and maintenance of synaptic connections.     

The role of apolipoprotein E in lipid metabolism in the central nervous system

The critical roles of apolipoprotein E (apoE) in regulating plasma lipid and lipoprotein levels have been extensively studied for over 2 decades. However, an understanding of the roles of apoE in the central nervous system (CNS) is less certain. This review will summarize the available experimental results on the role of apoE in CNS lipid homeostasis with respect to its modulation of sulfatide trafficking, alteration of CNS cholesterol homeostasis and apoE-induced changes in phospholipid molecular species in specialized subcellular membrane fractions. The results indicate that apoE mediates sulfatide trafficking and metabolism in the CNS. Moreover, although apoE does not affect the cholesterol mass content or the phospholipid mass levels and composition in the CNS as a whole, apoE modulates cholesterol and phospholipid homeostasis in selective subcellular membrane compartments. Through elucidating the roles of apoE in CNS lipid metabolism, new insights into overall functions of apoE in neurobiology can be accrued ultimately, leading to an increased understanding of CNS lipid metabolism and the identification of novel therapeutic targets for CNS diseases.Received 9 January 2004; received after revision 28 February 2004; accepted 10 March 2004     

Central nervous system stem cells in the embryo and adult

The central nervous system is generated from neural stem cells during embryonic development. These cells are multipotent and generate neurons, astrocytes and oligodendrocytes. The last few years it has been found that there are populations of stem cells also in the adult mammalian brain and spinal cord. In this paper, we review the recent development in the field of embryonic and adult neural stem cells. Received 26 March 1998; received after revision 27 April 1998; accepted 27 April 1998     

Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system

In this review, we summarize the structure and function of the scavenger receptor family of proteins including class A (type I and II macrophage scavenger receptors, MARCO), class B (CD36, scavenger receptor class BI), mucinlike (CD68/macrosialin, dSR-CI) and endothelial (LOX-1) receptors. Two motifs have been identified as ligand-binding domains a charged collagen structure of type I and II receptors, and an immunodominant domain of CD36. These structures can recognize a wide range of negatively charged macromolecules, including oxidized low-density lipoproteins, damaged or apoptotic cells, and pathogenic microorganisms. After binding, these ligands can be either internalized by endocytosis or phagocytosis, or remain at the cell surface and mediate adhesion or lipid transfer through caveolae. Under physiological conditions, scavenger receptors serve to scavenge or clean up cellular debris and other related materials, and they play a role in host defence. In pathological states, they mediate the recruitment, activation and transformation of macrophages and other cells which may be related to the development of atherosclerosis and to disorders caused by the accumulation of denatured materials, such as Alzheimer's disease. Received 17 September 1997; received after revision 16 March 1998; accepted 17 March 1998     

Ecdysteroid receptors located in the central nervous system of an insect

Summary Using thaw-mount autoradiography for steroid hormones, we obtained direct evidence for a nuclear localization of ecdysteroid binding sites in target organs of blowfly (Calliphora vicina) larvae. The binding sites revealed properties of ecdysteroid receptors. Endocrine cells of the ring gland were found to be target tissues of ecydysteroids. This observation provides morphological evidence for a network of complex interendocrine regulation. In the central nervous system receptorcontaining neurons were identified which include many, if not all, neurosecretory cells of the brain. A map of ecdysteroid sensitive cells of the larval brain is presented.     

Degeneration of the peripheral and central nervous system in vitamin-B12-deficient monkeys

Resumen Monos cautivos mantenidos en una dieta vegetariana presentaron niveles séricos de vitamina B₁₂ reducidos y lesiones en el sistema nervioso central semejantes a las de la «degeneración combinada sub aguda» del humano. Los nervios periféricos mostraron desmielinización segmentaria, compatible con un compromiso de las células de Schwann al azar. Usualmente hubo remielinización segmentaria, asociada a veces con degeneración axónica (walleriana). No se encontró evidencia de remielinización o de regeneración axónica que pudiera ser atribuída totalmente al tratamiento con vitamina B₁₂.     

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.     

Tetanus intoxication causes an increment of serotonin in the central nervous system

Summary Mice injected with tetanus toxin (TTx) showed an increase of 5-hydroxytryptamine (serotonin, 5-HT) levels in the central nervous system. The increment was not uniform thoughout the central nervous system. Particularly significant were the 25% and 80% increases observed, respectively, in whole brain and spinal cord. The levels of dopamine and norepinephrine remained unchanged. The subsequent studies of 5-HT turnover revealed a synthesis rate in the tetanic animals that was almost double that of controls. The degradation rate of the amine as well as the levels of 5-hydroxyindolacetic acid were unaffected.     

Migratory patterns of clonally related cells in the developing central nervous system

Summary Neurons and glioblasts that arise in the ventricular zone migrate to form discrete nuclei and laminae as the central nervous system develops. By stably labeling precursor cells in the ventricular zone, pathways taken by different cells within an individual clone can be described. We have used recombinant retroviruses to label precursor cells with a heritable marker, theE. coli lacZ gene; clones of lacZ-positive cells are later mapped histochemically. Here we review results from three regions of the chicken central nervous system — the optic tectum, spinal cord, and forebrain - and compare them with previous results from mammalian cortex and other regions of the vertebrate CNS. In particular, we consider the relationship between migratory patterns and functional organization, the existence of multiple cellular sources of migratory guidance, and the issue of whether a cell's choice of migratory pathway influences its ultimate phenotype.     

Interaction of serotonin and lysergic acid diethylamide (LSD) in the central nervous system

Zusammenfassung Serotonin (5-Oxytryptamin) wirkt bei der Maus als mildes Sedativum und steigert den hypnotischen Effekt von Evipan deutlich. Diese Wirkungssteigerung kann durch Lysergsäure-diäthylamid (LSD) antagonisiert werden. Dieser Befund stimmt mit der Ansicht überein, dem Serotonin komme eine physiologische Rolle im Gehirn zu und dass LSD möglicherweise durch antagonistische Wirkung gegenüber Serotonin Psychose verursachen kann.