Differential Expression Analysis of the SLIT Family in Different Brain Regions

The ageing human brain undergoes extensive remodelling of its extracellular matrix (ECM), yet the regional specificity and molecular drivers remain poorly defined. Here we combine bulk RNA-sequencing of post-mortem tissue (n = 63 across eight regions) with independent validation in the Genotype-Tissue Expression (GTEx) cohort (n = 962) to chart the expression landscape of the 239-member core matrisome. Hippocampus emerged as a major ECM outlier, with 114 matrisome genes—dominated by glycoproteins—up-regulated compared to the other seven regions (Fisher’s combined test, FDR < 0.05). Genes coding the axon-guidance ligands SLIT1, SLIT2 and SLIT3 ranked among the top hippocampal signatures and displayed strong co-expression with ROBO2 (r > 0.70). Age-stratified analysis in GTEx revealed a concerted decline of the SLIT-ROBO2 axis after 60y, aligning with hallmarks of cognitive ageing. Immunohistochemistry and western blotting (n = 3 per region) supported regional and subcellular patterns of SLITs ROBO2. These findings identify the SLIT-ROBO2 module as a hippocampus-centric, age-labile component of the human matrisome. We propose that sustained SLIT-ROBO signalling supports hippocampal synaptic plasticity, whereas its late-life attenuation may diminish structural resilience and heighten vulnerability to neurodegeneration. Our resource provides a framework for targeting ECM pathways to preserve brain connectivity during ageing.