RESUMEN
In the context of aging and age-associated neurodegenerative disorders, the brain's extracellular matrix (ECM) serves as a critical regulator for neuronal health and cognitive function. Within the extracellular space, proteoglycans and their glycosaminoglycan attachments play essential roles in forming, stabilizing, and protecting neural circuits throughout neurodevelopment and adulthood. Recent studies in rodents reveal that chondroitin sulfate-glycosaminoglycan (CS-GAG) containing perineuronal nets (PNNs) exhibit both structural and compositional differences throughout the brain. While animal studies are illuminating, additional research is required to translate these interregional PNN/CS-GAG variations to human brain tissue. In this perspective article, we first investigate the translational potential for interregional CS-GAG variances across species as novel targets for region-specific therapeutic development. We specifically focus on the observation that alterations in brain PNN-associated CS-GAGs have been linked with the progression of Alzheimer's disease (AD) neuropathology in humans, but these changes have not been fully recapitulated in rodent models of this disease. A second highlight of this perspective article investigates whether AD-associated shifts in CS-GAGs in humans may be dependent on region-specific baseline differences in CS-GAG sulfation patterning. The current findings begin to disentangle the intricate relationships between the interregional differences in brain PNN/CS-GAG matrices across species, while emphasizing the need to better understand the close relationship between dementia and changes in brain CS-GAG sulfation patterns in patients with AD and related dementias.
RESUMEN
The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.