Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives

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Main idea: It is now clear that α-synuclein-associated inflammation contributes to the pathophysiology of PD  but research on whether or how α-synuclein modulates the function of macrophages in the brain has been mostly focused on microglia. As a result, our knowledge of the role of α-synuclein in other brain resident macrophages such as BAMs or other perivascular cells is poor. Similarly, despite the presence of studies indicating the interplay between ECs and microglia, the interplay between perivascular cells and ECs has been scarcely studied. For instance, since recent evidence showed that BAMs and microglia can acquire distinct genetic and molecular phenotypes early in development, studying whether α-synuclein plays a role in modulating the signaling pathways mediating the crosstalk between BAMs and ECs could bring novel and significant insights for understanding the biological basis of neurological disorders such as PD or stroke. Similarly, though α-synuclein transfer between cells and across BBB interfaces has been established, whether and how BAMs are involved in this event also deserves further investigations.

Abstract

Misfolded proteins, inflammation, and vascular alterations are common pathological hallmarks of neurodegenerative diseases. Alpha-synuclein was identified as a major component of Lewy bodies and Lewy neurites in the brain of patients affected by Parkinson’s disease (PD), Lewy body dementia (LBD), and other synucleinopathies. Recent evidence supports that the pathological forms of the protein can reduce the release of vasoactive and inflammatory mediators from endothelial cells and modulates the expression of tight junction (TJ) proteins. Border-associated macrophages (BAMs) are brain resident macrophage cells found in association with the vasculature, meninges, and choroid plexus. Recent findings indicate that these cells play distinct roles in stroke and neurodegenerative disorders. This review aims at summarizing the main findings supporting how α-synuclein can affect ECs and/or BAMs function. Gaps of knowledge on how this protein can contribute to neurodegeneration by inducing BBB homeostatic changes are highlighted.

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