Interconnected roles of astrocytes and the blood-brain barrier in Parkinson's disease: pathological evidence, mechanistic insights, and knowledge gaps.

Research overview

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Parkinson's disease (PD) has long been defined by α-synuclein aggregation and dopaminergic neurodegeneration, yet growing evidence indicates that non-neuronal contributors, specifically astrocytes and the blood-brain barrier (BBB), may play key roles in disease progression. Human neuropathological studies reveal BBB disruption and astrocytic abnormalities, including plasma protein extravasation, tight junction alterations, and microvascular degeneration in the substantia nigra and striatum, while neuroimaging and fluid biomarkers such as elevated QAlb, plasma GFAP, and CSF S100B further support in vivo vascular compromise and astrocytic reactivity. Complementary postmortem analyses highlight region- and stage-specific changes in both astrocytes and the vasculature. Mechanistic evidence from animal and cell-based models, including α-synuclein preformed fibrils, transgenic strains, and toxin-induced paradigms, demonstrates that BBB breakdown can precede or parallel dopaminergic loss, accompanied by disrupted astrocyte morphology, impaired end-feet polarization, and altered inflammatory and angiogenic signaling. Experimental manipulation of astrocytic pathways in these systems can either exacerbate or mitigate BBB dysfunction, underscoring a bidirectional astrocyte-vascular axis in PD pathology. Together, these findings position BBB and astrocytic dysfunction as intertwined processes that may amplify neurodegeneration, while underscoring critical gaps, including limited longitudinal human data, uncertain temporal ordering, and the need for integrative multimodal approaches, that must be addressed to determine whether astrocyte, BBB dysfunction drives disease progression or represents a secondary response, and whether it can be targeted for therapeutic intervention.

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