heparitin-sulfate and Nerve-Degeneration

Topics: Aggrecans; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Autoantibodies; Autoimmune Diseases; Blood-Brain Barrier; Brain; Capillaries; Cell Death; Chondroitin Sulfate Proteoglycans; Extracellular Matrix Proteins; Glycoproteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunoglobulin G; Lectins, C-Type; Models, Biological; Nerve Degeneration; Protein Processing, Post-Translational; Proteoglycans; Rats

Proper arrangement of axonal projections into topographic maps is crucial for brain function, especially in sensory systems. An important mechanism for map formation is pretarget axon sorting, in which topographic ordering of axons appears in tracts before axons reach their target, but this process remains poorly understood. Here, we show that selective axon degeneration is used as a correction mechanism to eliminate missorted axons in the optic tract during retinotectal development in zebrafish. Retinal axons are not precisely ordered during initial pathfinding but become corrected later, with missorted axons selectively fragmenting and degenerating. We further show that heparan sulfate is required non-cell-autonomously to correct missorted axons and that restoring its synthesis at late stages in a deficient mutant is sufficient to restore topographic sorting. These findings uncover a function for developmental axon degeneration in ordering axonal projections and identify heparan sulfate as a key regulator of that process.

Topics: Adenylyl Imidodiphosphate; Animals; Animals, Genetically Modified; Cell Movement; Coloring Agents; Embryo, Nonmammalian; Functional Laterality; Gene Expression Regulation, Developmental; Green Fluorescent Proteins; Heparitin Sulfate; HSP70 Heat-Shock Proteins; In Vitro Techniques; Microscopy, Confocal; Morpholinos; Mutation; Nerve Degeneration; Proteoglycans; Retina; Retinal Ganglion Cells; Time Factors; Tumor Suppressor Protein p53; Visual Pathways; Zebrafish; Zebrafish Proteins

This study shows that cotreatment with insulin-like growth factor-I (IGF-I) and glycosaminoglycans (GAGs) prevents the onset of neuromuscular deficit in the m/m mutant mouse. These mice show a mid-to-late-life onset of progressive paralysis of the hind limb, that is correlated with altered innervation and reduced nerve-evoked isometric twitch tension in the extensor digitorum longus (EDL) muscle. Almost 50% of EDL nerve endings are negative for antisynaptophysin staining, while retrograde labelling with beta-cholera-toxin coupled to type IV horseradish and quantitative histological analysis show a small loss of EDL and lumbar cord motor neurons. At 10 months of age also forelimb function evaluated as grip strength is significantly reduced. Animals treated either with glycosaminoglycans alone or with IGF-I alone at low and high doses showed only a partial improvement of their condition. However, cotreatment of m/m mice with IGF-I and GAGs fully prevented the neuromuscular abnormalities, the twitch tension loss, the motor neuron decrease and the reduction of forelimb grip strength.

Topics: Animals; Atrophy; Cell Count; Cholera Toxin; Dermatan Sulfate; Drug Therapy, Combination; Female; Fluorescent Dyes; Heparitin Sulfate; Horseradish Peroxidase; Insulin-Like Growth Factor I; Male; Mice; Mice, Neurologic Mutants; Motor Neurons; Muscle Fibers, Skeletal; Muscle, Skeletal; Nerve Degeneration; Neuromuscular Diseases; Neuroprotective Agents; Presynaptic Terminals; Rhodamines; Synaptophysin

beta-Amyloid peptide has been reported to be toxic to neurons in vitro and in vivo. The fragment of the beta 1-42 peptide believed to be responsible for this toxicity consists of amino acids 25 to 35. beta-amyloid protein, heparan sulfate (HS) glycosaminoglycan (GAG), and proteoglycan (PG) are all localized throughout the senile plaques found in Alzheimer's disease. Chondroitin sulfate (CS) and dermatan sulfate have also been found at the periphery of senile plaques. We have found that both HS and CS prevented neurite fragmentation and toxicity normally induced by beta 25-35. HS and CS by themselves did not have a significant influence on cell viability, indicating that their protective actions were not due to a general trophic effect. In contrast, cultures treated with HS and beta 1-42 did not show significantly reduced toxicity compared to cultures treated with beta 1-42 alone despite specific binding interactions. These data indicate that one function of GAGs in the brain may be to protect neurons from select toxic insults and injury, and additionally suggest that HS interacts differently with different beta-amyloid fragments. These data further suggest that different beta-amyloid fragments may induce distinct mechanisms of toxicity in vitro.

Topics: Amyloid beta-Peptides; Animals; Cell Survival; Cells, Cultured; Chondroitin Sulfates; Heparitin Sulfate; Hippocampus; Nerve Degeneration; Neurons; Peptide Fragments; Rats; Rats, Sprague-Dawley