Abstract
Misfolded proteins, inflammation, and vascular alterations are common pathological hallmarks of neurodegenerative diseases. Alpha-synuclein is a small synaptic protein that 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. It is mainly involved in the regulation of synaptic vesicle trafficking but can also control mitochondrial/endoplasmic reticulum (ER) homeostasis, lysosome/phagosome function, and cytoskeleton organization. Recent evidence supports that the pathological forms of α-synuclein can also reduce the release of vasoactive and inflammatory mediators from endothelial cells (ECs) and modulates the expression of tight junction (TJ) proteins important for maintaining the blood–brain barrier (BBB). This hints that α-synuclein deposition can affect BBB integrity. Border associated macrophages (BAMs) are brain resident macrophages found in association with the vasculature (PVMs), meninges (MAMs), and choroid plexus (CPMs). Recent findings indicate that these cells play distinct roles in stroke and neurodegenerative disorders. Although many studies have addressed how α-synuclein may modulate microglia, its effect on BAMs has been scarcely investigated. This review aims at summarizing the main findings supporting how α-synuclein can affect ECs and/or BAMs function as well as their interplay and effect on other cells in the brain perivascular environment in physiological and pathological conditions. Gaps of knowledge and new perspectives on how this protein can contribute to neurodegeneration by inducing BBB homeostatic changes in different neurological conditions are highlighted.
Highlights
Neurodegenerative diseases represent a relevant health burden, especially considering the growing population of elderly subjects
This event can negatively impinge on axonal projections, slowly flowing in a retrograde neurodegenerative process culminating in neuronal cell death [6,7,8]
Α-synuclein-related neuroinflammation, microglia activation, and vascular degeneration [9,10,11,12] have been described as important players in disease pathogenesis. This notwithstanding, whether α-synuclein communicates with other neurovascular components such as border-associated macrophages (BAMs) and vascular endothelial cells (ECs), which are involved in the early phases of ischemic brain damage [13,14,15,16], remains to be explored
Summary
Neurodegenerative diseases represent a relevant health burden, especially considering the growing population of elderly subjects. Erythrocyte-derived exosomes containing α-synuclein from patients with PD induce microglial activation in vivo and in vitro, suggesting that erythrocyte-derived extravasated α-synuclein may play a role in disease pathogenesis [121] These evidences support that further studies are needed to understand how exosomeassociated physiological or pathological forms of the protein may impact on brain immune cells and ECs function and on BBB integrity. Further studies are needed to corroborate whether and how α-synuclein deposition affects these cells, these findings, when coupled to the aforementioned noxious effects exerted by pathological α-synuclein on ECs, support that perivascular accumulation of the protein, by inducing ECs activation may compromise brain vessels integrity exacerbating astrocyte and microglia activation promoting neurodegeneration and BBB disruption (Figure 4)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
