Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate

Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establishment and maintenance of a neurogenic niche enriched with precisely balanced growth factors, morphogens and extracellular matrix proteoglycans (PGs) to support neuronal development and function. Membrane-bound heparan sulphate (HS) PGs consist of core proteins decorated with HS glycosaminoglycan side chains, whose highly variable sulphation patterns regulate cellular signalling pathways such as Wnt and fibroblast growth factor. However, the specific contributions of astrocyte-derived and/or neuronal HSPGs within this microenvironment remain unclear. This mini-review examined our current understanding of the regulatory role of astrocyte-expressed HSPGs and their associated HS side chain structural variability. In particular, their influence on prenatal brain development, ageing and the changes occurring that contribute to neurodegeneration. We focused on the emerging concept that HS aggregation and impaired neurogenesis may serve as important preclinical contributors to Alzheimer's disease pathology. Alterations in astrocyteexpressed HS and their HSPG landscape are discussed as potential precursors to pathological HS aggregation and reactivity, shifting the focus of disease initiation to the potential compromise of the supportive astrocytic environment. We suggest that neuronal dysfunction cannot be solely attributed to neurodegeneration but must also be considered in the context of a deteriorating support system, where cells that once nurtured neurogenesis and synaptic integrity become dysfunctional contributors to disease pathology.