Age-Related Changes in Matrix Metalloproteinase-9 Expression in Spinal Motor Neurons of Normal Mice

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs). Although the cause of motor neuron (MN) degeneration in patients with ALS remains unknown, certain MN types (such as oculomotor neurons) and MNs within the Onuf (Onuf-Mannen) nucleus are preserved until the terminal stage. We previously generated mice with a selective knockout of adenosine deaminase acting on RNA 2 (ADAR2) in cholinergic neurons (ADAR2^flox/flox /vesicular acetylcholine transporter (VAChT)-Cre.Fast; AR2). AR2 mice exhibit slow progressive loss of LMNs accompanied by TAR DNA-binding protein 43 (TDP-43) pathology against a background of insufficient editing at the GluA2 glutamine/arginine (Q/R) site due to ADAR2 deficiency. This model confirmed that insufficient editing at the GluA2 Q/R site, due to reduced ADAR2 activity, contributes to the pathogenesis of ALS. Furthermore, in AR2 mice, more frequent death of fast-fatigable motor neurons (FF MNs) was observed owing to differences in vulnerability under ADAR2-deficient conditions. Similar changes were observed during normal aging in the control mice. These findings suggest that investigating the characteristics of FF MNs may be useful for analyzing neuronal death in ALS. Recently, matrix metalloproteinase-9 (MMP-9), a marker of FF MNs, was reported to induce neurodegeneration. However, the distribution of MMP-9 in normal spinal MNs and its age-related changes remain unclear. Therefore, we investigated the MMP-9 expression patterns in normal mice at six and 12 months of age. In the present study, the number of MNs in the anterior horn (AH) decreased with age, as did the number of MMP-9-positive MNs. Furthermore, as aging has been shown to induce the abnormal localization of TDP-43 in MMP-9-positive MNs, these MNs were considered vulnerable to degeneration. These findings suggest that MMP-9 not only functions as a marker for FF MNs but may also act as a potentially useful marker for MNs prone to degeneration with TDP-43 pathology, or for early degeneration in both physiological aging and age-related diseases, including ALS. Future investigations of MMP-9 expression in patients with ALS and in ALS mouse models are considered useful for elucidating ALS pathogenesis.