TENASCIN-R IS ANTIADHESIVE FOR ACTIVATED MICROGLIA THAT INDUCE DOWN-REGULATION OF THE PROTEIN AFTER PERIPHERAL-NERVE INJURY - A NEW ROLE INNEURONAL PROTECTION

Microglial activation in response to pathological stimuli is character ized by increased migratory activity and potential cytotoxic action on injured neurons during later stages of neurodegeneration. The initial molecular changes in the CNS favoring neuronofugal migration of micro glia remain, however, largely unknown. We report that the extracellula r matrix protein tenascin-R (TN-R) present in the intact CNS is antiad hesive for activated microglia, and its downregulation after facial ne rve axotomy may account for the loss of motoneuron protection and subs equent neurodegeneration. Studies on the protein expression in the fac ial and hypoglossal nucleus in rats demonstrate that TN-R is a constit uent of the perineuronal net of motoneurons and 7 d after peripheral n erve injury becomes downregulated in the corresponding motor nucleus. This downregulation is reversible under regenerative (nerve suture) co nditions and irreversible under degenerative (nerve resection) conditi ons. In short-term adhesion assays, the unlesioned side of brainstem c ryosections from unilaterally operated animals is nonpermissive for ac tivated microglia, and this nonpermissiveness is almost abolished by a monoclonal antibody to TN-R, Microglia-conditioned media and tumor ne crosis factor-ct downregulate TN-R protein and mRNA synthesis by cultu red oligodendrocytes, which are one of the sources for TN-R in the bra instem. Our findings suggest a new role for TN-R in neuronal protectio n against activated microglia and the participation of the latter in p erineuronal net destruction, e.g,, downregulation of TN-R.