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Proteoglycans are highly specialized proteins with specific interactive modules in their core proteins, allowing them to engage with a diverse range of cellular and structural proteins, contributing to many varied roles in cell processes. This review examines the roles of heparan sulfate (HS) proteoglycans (HSPGs) in the assembly of pathological protein aggregates in brain tissues, which negatively impact cognitive brain function. While HSPGs play roles in normal brain development, they also contribute to the abnormal accumulation and persistence of protein aggregates in Alzheimers and Parkinsons diseases (AD and PD), prolonging their neurotoxic effects. HSPG-mediated effects on the innate immune system may also contribute to the development of neuroinflammation and pathogenesis of neurodegenerative changes in the central nervous system. These pathological developments lead to impaired cognition, permanent memory loss in dementia and AD, and an inability of the brain to exert normal neuromuscular control, affecting motor functions and body movement in PD. A deeper understanding of the properties of HS in these degenerative processes is essential for the development of therapeutic measures to treat these conditions. Significant improvements in neuroimaging, next-generation glycosaminoglycan analytical techniques, and functional glycomics hold great promise for elucidating the complexities of HS structure and function. These advancements may significantly aid in the development of HS biotherapeutics to treat these debilitating conditions, which are increasingly impacting the aging global population. While a number of promising therapeutic candidates have already emerged, further research is required to optimize their biotherapeutic applications in this challenging area of pathobiology, bioregulation, and the recovery of neural function.
Melrose et al. (Wed,) studied this question.