Toxic Alpha-Synuclein and the Opening of the Gate: Blood–Brain Barrier Damage and Stepwise Leukocyte Infiltration

α-Synucleinopathies are characterized by the pathological accumulation of misfolded α-synuclein (α-syn). In addition to its well-established neuronal toxicity, growing evidence suggests that α-syn may be associated with alterations in vascular and immune processes that contribute to neurodegeneration. Increasing attention has been directed toward the neurovascular unit and blood–brain barrier (BBB) as potential sites of early dysfunction, which may facilitate interactions between the central nervous system and peripheral immune compartments. However, the temporal sequence of these events and the relative contributions of specific immune cell populations remain incompletely defined. Experimental and clinical studies indicate that toxic α-syn species can affect endothelial and pericyte function, disrupt tight junction organization, and alter neurovascular signaling, potentially increasing BBB permeability. Such changes may allow the entry of peripheral immune cells into the brain parenchyma, where infiltrating lymphocytes—including Th1, Th17, and cytotoxic T cells—have been reported to contribute to neuroinflammatory responses through cytokine production, antigen-specific interactions, and modulation of microglial activity. In contrast, regulatory T cells may exert limited immunomodulatory effects, while monocytes and monocyte-derived macrophages appear capable of adopting either neurotoxic or neuroprotective phenotypes depending on the local inflammatory milieu. Emerging data further suggest that neutrophils and neutrophil extracellular traps (NETs) may participate in early vascular inflammation and BBB alterations, potentially influencing subsequent immune cell recruitment. Here, we review multiple, potentially complementary mechanisms that have been proposed to underlie BBB dysfunction and immune cell infiltration in α-synucleinopathies. By integrating neurovascular and immunological perspectives, this review aims to highlight the complex and dynamic interplay between vascular compromise and immune responses, and to discuss therapeutic strategies targeting the neurovascular unit and pathological immunity. Peripheral immune cells in α-synuclein-induced neurodegeneration. Toxic α-synuclein disrupts the neurovascular unit and blood–brain barrier, enabling infiltration of peripheral immune cells. These cells drive microglial activation and proinflammatory polarization (M1). α-Synuclein also directly activates microglia and damages astrocytes. Activated microglia stimulate Th1 cells to produce cytokines, forming a feed-forward inflammatory loop that accelerates neurodegeneration in α-synucleinopathies. Created with BioRender.com.