LUMBAR FRACTALKINE AND M2 MICROGLIA INCREASE THROUGHOUT DISEASE PROGRESSSION IN CANINE DEGENERATIVE MYELOPATHY

摘要

Canine degenerative myelopathy (DM) is an adult-onset neurodegenerative disorder. Clinical progression is homogeneous within and across breeds, thus four distinct disease stages have been identified (Kanazono et al., 2013, Coates and Wininger, 2010).DM shares similarities with some forms of amyotrophic lateral sclerosis (ALS), including underlying mutations in superoxide dismutase-1 (SOD1). SOD1-mutant microglia play a central role in ALS progression in rodent models. Microglia behavior is complex,as expression patterns of classic M1 and M2 molecules are variable throughout disease and between species studied. The mechanism(s) underlying microglial phenotype determination within ALS is not known. Fractalkine, a neuronally produced chemokine, has been shown to suppress SOD1 mutant microglial-mediated neurotoxicity in vitro. Thus, fractalkine is a possible contributor to microglial phenotype determination in ALS. Increased spinal cord microglia have been documented in end-stage DM-affected dogs, however, their response and phenotype throughout disease progression is unknown. The goals of this study were to 1) quantify and phenotype microglial cells in close proximity to lumbar spinal cord motor neurons of DM-affected dogs at each disease stage and compare these findings to age-matched, neurologically normal dogs and 2) correlate microglial phenotype with fractalkine protein levels in lumbar spinal cord throughout disease progression.