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<p>Neuroinflammation and ECM remodeling have been identified as the main factors leading to cognitive decline in both neurodegenerative and neuropsychiatric disorders. Proteoglycans and GAGs represent the greatest functional elements of ECM in synaptic stability, neuroimmune signaling, blood-brain barrier integrity, and protein aggregation. These molecules, which exhibit various sulfation patterns and chain structures, are able to modulate cytokine gradients, growth factor signaling, complement activation, and redox balance dynamically. Under normal conditions, they help maintain CNS homeostasis through neuronal plasticity and glial response coordination. Nevertheless, disease-driven variations in GAG makeup and sulfation patterns may result in increased inflammatory cascades, amyloid, and tau aggregation, synuclein spreading, and synaptic flexibility loss. Perineuronal nets, GAG, contained ECM structures, demonstrating the twofold functions of proteoglycans in memory preservation and plasticity limitation. Besides that, they also aggravate the aging process in brain by making ECM harder and more fragmented through inflammatory lysis. Therapeutic strategies directly targeting GAGs and proteoglycans, including enzymatic modulation, GAG mimetics, sulfation, specific interventions, and biomaterial, mediated delivery systems, represent attractive options for the restoration of tissue homeostasis. The glycosaminoglycan field indeed grapples with challenges such as structural diversity and complexity, context, dependent biological effects, and difficulties in clinical application; however, glycomics, systems biology, and precision neurotherapeutics developments are facilitating the emergence of extracellular matrix, targeting treatments. Altogether, the review elaborates on the mechanistic as well as clinical importance of glycosaminoglycans and proteoglycans in neuroinflammation and cognitive deterioration, and points to their utility as both disease biomarkers and therapeutic targets in neurodegenerative disorders.</p>

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Glycosaminoglycans and proteoglycans: emerging macromolecular targets in neuroinflammation and cognitive decline

  • 期刊论文

  • 发表日期：

    2026年7月25日

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  • Falguni Goel,
  • Prateek Gupta,
  • Shipra Karthik,
  • Payal Singh,
  • Sachchida Nand Rai

摘要

Neuroinflammation and ECM remodeling have been identified as the main factors leading to cognitive decline in both neurodegenerative and neuropsychiatric disorders. Proteoglycans and GAGs represent the greatest functional elements of ECM in synaptic stability, neuroimmune signaling, blood-brain barrier integrity, and protein aggregation. These molecules, which exhibit various sulfation patterns and chain structures, are able to modulate cytokine gradients, growth factor signaling, complement activation, and redox balance dynamically. Under normal conditions, they help maintain CNS homeostasis through neuronal plasticity and glial response coordination. Nevertheless, disease-driven variations in GAG makeup and sulfation patterns may result in increased inflammatory cascades, amyloid, and tau aggregation, synuclein spreading, and synaptic flexibility loss. Perineuronal nets, GAG, contained ECM structures, demonstrating the twofold functions of proteoglycans in memory preservation and plasticity limitation. Besides that, they also aggravate the aging process in brain by making ECM harder and more fragmented through inflammatory lysis. Therapeutic strategies directly targeting GAGs and proteoglycans, including enzymatic modulation, GAG mimetics, sulfation, specific interventions, and biomaterial, mediated delivery systems, represent attractive options for the restoration of tissue homeostasis. The glycosaminoglycan field indeed grapples with challenges such as structural diversity and complexity, context, dependent biological effects, and difficulties in clinical application; however, glycomics, systems biology, and precision neurotherapeutics developments are facilitating the emergence of extracellular matrix, targeting treatments. Altogether, the review elaborates on the mechanistic as well as clinical importance of glycosaminoglycans and proteoglycans in neuroinflammation and cognitive deterioration, and points to their utility as both disease biomarkers and therapeutic targets in neurodegenerative disorders.