Cystatin C and its Role in the Neuro-Glial-Vascular Unit: Implications for Cerebrovascular Diseases and Neurodegeneration.

Cystatin C (CysC) is emerging as a key regulator and intercellular signaling mediator within the neuro-glial-vascular unit (NGVU). This review comprehensively examines its multifaceted roles across NGVU components, detailing mechanisms by which CysC preserves blood-brain barrier integrity, modulates neuroinflammation, and influences pathological protein aggregation. Rather than providing a merely descriptive catalogue, we emphasize its context-dependent nature. In cerebrovascular and neurodegenerative diseases, CysC exhibits functional duality along the neuron-glia axis, either restraining or perpetuating inflammation and proteinopathy depending on cellular context and disease stage. Similarly, along the endothelial-oligodendrocyte precursor cell crosstalk, its coordination of angiogenesis and myelination may shift from protective to detrimental under chronic hypoperfusion. We evaluate its dual utility as a clinical biomarker and therapeutic target, addressing challenges in brain delivery, target selectivity, and safety. This integrative synthesis provides a critical perspective on unresolved controversies and future research priorities regarding CysC in neurological disorders.