Differential microglial response to progressive neurodegeneration in the murine mutantwobbler

Abstract

Activated microglia is associated with neurodegenerative processes, but the precise role of this cell population is difficult to identify. Most experimental models employed to examine microglial responses involve acute alterations of neuronal integrity, in contrast to the progressive nature of neurodegenerative diseases. In order to approach the clinical situation better, the microglial response was analyzed in the murine mutant Wobbler, which exhibits a well-characterized neurodegenerative pathology, manifested by motoneuronal death following a period of cellular dysfunction with characteristic morphological features. Microglial cells were identified using anti-Mac1 or anti-IgG antibodies. Examination of the changes in density, localization, and phenotype of microglia differentiated two types of responses in Wobblers. A first type of response was observed as early as in the third week after birth, when the only apparent neuronal defect was the morphological alteration of a subset of motoneurons in the cervical spinal cord, which was maintained later on. The activated microglia extended long processes that selectively ensheathed vacuolated motoneurons. At later stages, when motoneuron death became prominent, an additional type of response was characterized by an increased density of reactive microglia that was seen extending throughout the cervical enlargement. This secondary microglial response occurred in parallel to the infiltration of T-lymphocytes. Thus, these results point to a differential response of microglial cells to a progressive neurodegenerative process.