Central nervous system (CNS) accumulation of fibrillary deposits made of Amyloid β (Aβ), hyperphosphorylated Tau or α-synuclein (α-syn), present either alone or in the form of mixed pathology, characterizes the most common neurodegenerative diseases (NDDs) as well as the aging brain. Compelling evidence supports that acute neurological disorders, such as traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition of toxic Aβ, Tau and α-syn species. While the contribution of these pathological proteins to neurodegeneration has been experimentally ascertained, the cellular and molecular mechanisms driving Aβ, Tau and α-syn-related brain damage remain to be fully clarified. In the last few years, studies have shown that Aβ, Tau and α-syn may contribute to neurodegeneration also by inducing and/or promoting blood–brain barrier (BBB) disruption. These pathological proteins can affect BBB integrity either directly by affecting key BBB components such as pericytes and endothelial cells (ECs) or indirectly, by promoting brain macrophages activation and dysfunction. Here, we summarize and critically discuss key findings showing how Aβ, Tau and α-syn can contribute to BBB damage in most common NDDs, TBI and stroke. We also highlight the need for a deeper characterization of the role of these pathological proteins in the activation and dysfunction of brain macrophages, pericytes and ECs to improve diagnosis and treatment of acute and chronic neurological disorders.

中枢神经系统 (CNS) 由β淀粉样蛋白(A β )、过度磷酸化 Tau 或α-突触核蛋白 ( α -syn) 组成的纤维沉积物的积累，单独或以混合病理形式存在，是最常见的神经退行性疾病 (NDD) 的特征）以及老化的大脑。令人信服的证据表明，急性神经系统疾病，如创伤性脑损伤 (TBI) 和中风，也伴随着有毒 A β、Tau 和α -syn 物质沉积的增加。虽然这些病理蛋白对神经变性的贡献已通过实验确定，但驱动 A β、 Tau 和α -syn 相关脑损伤的细胞和分子机制仍有待完全阐明。过去几年的研究表明，A β、Tau 和α -syn 也可能通过诱导和/或促进血脑屏障 (BBB) 破坏而导致神经退行性变。这些病理蛋白可以通过影响周细胞和内皮细胞 (EC) 等关键 BBB 成分直接影响 BBB 完整性，也可以通过促进脑巨噬细胞激活和功能障碍间接影响 BBB 完整性。在这里，我们总结并批判性地讨论了一些关键发现，这些发现表明 A β、Tau 和α -syn 如何在最常见的 NDD、TBI 和中风中导致 BBB 损伤。我们还强调需要更深入地表征这些病理蛋白在脑巨噬细胞、周细胞和 EC 的激活和功能障碍中的作用，以改善急性和慢性神经系统疾病的诊断和治疗。