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

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Abstract
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.

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