Microglial-neuronal interactions are essential for brain physiopathology. In this framework, recent data have changed the concept of microglia from essentially macrophagic cells to crucial elements in maintaining neuronal homeostasis and function through the release of neuroprotective molecules. Using proteomic analysis, here we identify copper-zinc superoxide dismutase (SOD1) as a protein produced and released by cultured rat primary microglia. Evidence for a neuroprotective role of microglia-derived SOD1 resulted from experiments in which primary cerebellar granule neurons (CGNs) were exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA). Microglial conditioned medium, in which SOD1 had accumulated, protected CGNs from degeneration, and neuroprotection was abrogated by SOD1 inhibitors. These effects were replicated when exogenous SOD1 was added to a nonconditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. Further experiments demonstrated the specificity of SOD1 neuroprotection against 6-OHDA compared to other types of neurotoxic challenges. SOD1, constitutively produced and released by microglia through a lysosomal secretory pathway, is identified here for the first time as an essential component of neuroprotection mediated by microglia. This novel information is relevant to stimulating further studies of microglia-mediated neuroprotection in in vivo models of neurodegenerative diseases.

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Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.

/pdf/signaling-mechanisms-linking-neuronal-activity-to-gene-mhoakf9fuz.pdf

Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system.

In their Point of View entitled "Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis," Sriram and Steiner(1) wrote, "The most disappointing aspect of EAE [experimental allergic encephalomyelitis] as a potential model for MS is its almost total inability to point toward a meaningful therapy or therapeutic approach for MS." Actually, EAE has led directly to the development of three therapies approved for use in multiple sclerosis (MS): glatiramer acetate, mitoxantrone, and natalizumab. Several new approaches to MS are in clinical trials based on positive indications in preclinical work relying on EAE. New clues to the pathogenesis of MS and new potential surrogate markers for MS are shown from research involving EAE when it is critically coupled with actual findings in MS. There are pitfalls in overreliance on the EAE model, or on any animal model for any human disease. Nevertheless, over the past 73 years, the EAE model has proved itself remarkably useful for aiding research on MS.

/pdf/how-to-successfully-apply-animal-studies-in-experimental-2ceck5zr5a.pdf

How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis.

Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ± 7 days (n = 15) to 263 ± 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

https://www.pnas.org/content/pnas/100/8/4790.full.pdf

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

It is believed that a major reason for the poor functional recovery after peripheral nerve lesion is collateral branching and regrowth of axons to incorrect muscles. Using a facial nerve injury protocol in rats, we previously identified a novel and clinically feasible approach to combat axonal misguidance--the application of neutralizing antibodies against neurotrophic factors to the injured nerve. Here, we investigated whether reduced collateral branching at the lesion site leads to better functional recovery. Treatment of rats with antibodies against nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor, insulin-like neurotrophic factor I, ciliary neurotrophic factor or glial cell line-derived neurotrophic factor increased the precision of reinnervation, as evaluated by multiple retrograde labelling of motoneurons, more than two-fold as compared with control animals. However, biometric analysis of vibrissae movements did not show positive effects on functional recovery, suggesting that polyneuronal reinnervation--rather than collateral branching --may be the critical limiting factor. In support of this hypothesis, we found that motor end-plates with morphological signs of multiple innervation were much more frequent in reinnervated muscles of rats that did not recover after injury (51% of all end-plates) than in animals with good functional performance (10%). Because polyneuronal innervation of muscle fibres is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies could be soon designed and tested.

Factors limiting motor recovery after facial nerve transection in the rat: combined structural and functional analyses

The glycoproteins tenascin-C (TNC) and tenascin-R (TNR) are extracellular matrix proteins involved in the development, plasticity and repair of the nervous system Altered expression patterns after nerve lesions in adult animals have suggested that these molecules influence axonal regeneration To test this hypothesis, we investigated adult mice constitutively deficient in the expression of TNC, TNR or both, using the facial nerve injury paradigm Quantitative analysis of vibrissal movements prior to nerve transection and repair (facial-facial anastomosis) did not reveal genotype-specific differences, and thus impacts of the mutations on motor function in intact animals Two months after nerve repair, recovery of vibrissal whisking was poor in wild-type mice, a typical finding after facial-facial anastomosis in rodents Differential effects of the mutations on whisking were found: recovery of function was worse in TNC-deficient and better in TNR null mice compared with wild-type littermates In double-knockout animals, vibrissal performance was insufficient, but to a lesser extent compared with TNC null mutant mice Retrograde labelling of motoneurons in the same animals showed that similar numbers of motoneurons had reinnervated the whisker pads in all experimental groups precluding varying extents of motoneuron death and/or axon regeneration failures as causes for the different outcomes of nerve repair Our results provide strong evidence that TNC promotes and TNR impedes recovery after nerve lesion These findings are of particular interest with regard to the scanty knowledge about factors determining success of regeneration in the peripheral nervous system of mammals

Opposite impacts of tenascin-C and tenascin-R deficiency in mice on the functional outcome of facial nerve repair.

Erratum: Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis (Proceeding of the National Academy (April 15, 2003) 100: 8 (4790-4795))

Mithra Lenzen

Papers

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Factors limiting motor recovery after facial nerve transection in the rat: combined structural and functional analyses

Opposite impacts of tenascin-C and tenascin-R deficiency in mice on the functional outcome of facial nerve repair.

Erratum: Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis (Proceeding of the National Academy (April 15, 2003) 100: 8 (4790-4795))