Differential microglial response to progressive neurodegeneration in the murine mutant wobbler

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.

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

“…Marked activation of microglia and astrocytes, and cytokine overexpression (that is, TNF-α), were commonly detected in the SOD1 transgenic mouse (48)(49)(50) and in the wobbler mouse. The wobbler mouse shows earlyonset selective motor neuron death in the cervical spinal cord (37) accompanied by glial activation (21)(22)(23) and upregulation of TNF-α (24) and the activation of both jun N-terminal kinase (JNK) and p38 mitogen-activated stress kinase (p38MAPK) in glial cells and neurons at the early phases of symptom progression (38). The beneficial effect shown by the chronic treatment with a TNF-α binding protein (rhTBP-1; 38) further strengthens the primary role of inflammation in motor neuron degeneration in this model.…”

“…The wobbler mouse, carrying a mutation in the vacuolarvesicular protein sorting S4 (Vps54) gene (18) coding for a protein involved in the retrograde transport of late endosomes from the periphery to the Golgi apparatus (19), shows early-onset selective motor neuron death in the cervical spinal cord (reviewed in [20]). Glial activation (21)(22)(23) and upregulation of tumor necrosis factor (TNF)-α (24) have been reported in the cervical spinal cord of presymptomatic or early symptomatic mice. Thus, the wobbler mouse represents a useful model for testing candidate treatments aimed at modifying the neuroinflammatory mechanisms underlying the motor neuron loss.…”

Stage Dependent Effects of Progesterone on Motoneurons and Glial Cells of Wobbler Mouse Spinal Cord Degeneration

“…Morphologically, ventral horn motoneurons of Wobbler mice undergo a dramatic perikaryal vacuolar degeneration that is accompanied by astrocytosis and microglial activation (Boillée et al 2001(Boillée et al , 2003Hantaz-Ambroise et al 2001;Mitsumoto and Boggs 1987;Rathke-Hartlieb et al 1999). In this sense, mechanisms involved in motoneuron vacuolation are of primary importance to understand the ethiopathogenesis of the Wobbler disease.…”

Biochemistry and molecular biology education in Latin America and Iberia

“…This increase was not observed in wt animals. Microglial activation and proliferation is a stereotypical response to injury in the CNS and occurs in: focal brain ischemia (Hess et al, 2004; Priller et al, 2001), Alzheimer's disease (McGeer and McGeer, 2003), and motor neuron axotomy (Kalla et al, 2001; Priller et al, 2001), in addition to ALS and in several mouse models of ALS (Boillee et al, 2001; Hall et al, 1998). Our data show that microglia increase in number in areas of the CNS that are specific to neuron degeneration, consistent with previous studies (McGeer and McGeer, 2002).…”

“…These studies suggest that non‐neuronal cells are involved in the pathogenesis of ALS. Other studies have demonstrated that there are elevated numbers of microglia within the spinal cord and brain of mouse models of neurodegenerative disease (Boillee et al, 2001; Hall et al, 1998; Hess et al, 2002).…”