SASP-Secreted MMP-9 from Senescent Microglia Generates Pathological TDP-43 C-Terminal Fragments That Propagate ALS Pathology

The hypothesis proposes that MMP-9 (matrix metalloproteinase-9), secreted via the senescence-associated secretory phenotype (SASP) from senescent microglia, generates pathological C-terminal fragments of TARDBP (TDP-43) that propagate ALS pathology through cytoplasmic aggregation seeding. High-strength evidence from TDP-43 ALS mouse models demonstrates that reactive microglia expressing MMP-9 remodel perineuronal nets around motor neurons, suggesting a mechanistic link between MMP-9 expression and TDP-43 pathology. Additionally, genetic reduction of MMP-9 protects motor neurons from TDP-43-triggered degeneration in the rNLS8 ALS model, providing disease-model support for MMP-9 as a TDP-43 toxicity amplifier. Human ALS tissue contains disease-enriched C-terminal TDP-43 fragments measurable by targeted mass spectrometry, supporting the fragment endpoint in human disease, though the generating protease remains unidentified. Cell-model evidence further confirms that these C-terminal fragments aggregate readily and injure neurons, supporting their pathogenic relevance once generated. However, the mechanistic specificity of this pathway remains uncertain: a comprehensive biomarker study found MMP-9 alterations alongside other biomarkers in serum and CSF but found no evidence of MMP-9-mediated TDP-43 C-terminal fragmentation in ALS patients, suggesting MMP-9 elevation may reflect general neuroinflammation and blood-brain barrier breakdown rather than a specific cleavage mechanism. Furthermore, MMP-9 and its inhibitors TIMP-1/TIMP-2 are elevated in both serum and CSF of ALS patients, but similar elevations occur in other motor neuron diseases, indicating non-specificity for ALS pathology. Taken together, the evidence supports MMP-9 involvement in TDP-43-related neurodegeneration in model systems, but direct proof of MMP-9-mediated proteolytic cleavage of TDP-43 into C-terminal fragments in human ALS remains elusive.