Peripheral nerve inflammation in ALS mice: cause or consequence

Neuroinflammation is a prominent pathologic feature in the spinal cord of patients with amyotrophic lateral sclerosis (ALS), and is characterized by glial activation and infiltrating T cells.¹ A similar inflammatory response is present in spinal cords of ALS mice¹ and is preceded by evidence of a “dying back phenomenon” which includes motor axon degeneration and alterations of the neuromuscular junction.² The presence of monocytes/macrophages surrounding the degenerating peripheral nerve fibers is an early event that occurs prior to the onset of clinical signs of motor weakness,³ and thus raises the question whether the peripheral nerve inflammatory response initiates, or is in response to, the neurodegenerative process. To address this question, we evaluated the time course of denervation and accompanying inflammatory responses in the lumbar spinal cord–sciatic nerve–gastrocnemius and the cervical spinal cord–phrenic nerve–diaphragm motor units of ALS mice, and found that denervation occurred prior to inflammation; also, both denervation and inflammation occurred earlier in the sciatic nerve motor unit than in the phrenic nerve motor unit. Therefore, peripheral nerve inflammation is probably not the cause of denervation, but rather a response to the neurodegenerative process.