Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1 G93A ALS mouse model

• Published in: Neuropathology and applied neurobiology 2024-06, Vol.50 (3), p.e12982
• Main Authors: Cheung, Sang Won, Bhavnani, Ekta, Simmons, David G, Bellingham, Mark C, Noakes, Peter G
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Astrocytes - metabolism; Astrocytes - pathology; Disease Models, Animal; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Transgenic; Microglia - metabolism; Microglia - pathology; Motor Neurons - metabolism; Motor Neurons - pathology; Phagocytosis - physiology; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12982

Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1 strain, a fast-onset ALS mouse model. This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1 strain. We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1 mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1 mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1 mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1 mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1 mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death. Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1 ALS model mouse.