Kim Sehwan, Sharma Chanchal, Jung Un Ju, Kim Sang Ryong
School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
Brain Science and Engineering Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
Biomedicines. 2023 May 7;11(5):1383. doi: 10.3390/biomedicines11051383.
The blood-brain barrier (BBB) restricts entry of neurotoxic plasma components, blood cells, and pathogens into the brain, leading to proper neuronal functioning. BBB impairment leads to blood-borne protein infiltration such as prothrombin, thrombin, prothrombin kringle-2, fibrinogen, fibrin, and other harmful substances. Thus, microglial activation and release of pro-inflammatory mediators commence, resulting in neuronal damage and leading to impaired cognition via neuroinflammatory responses, which are important features observed in the brain of Alzheimer's disease (AD) patients. Moreover, these blood-borne proteins cluster with the amyloid beta plaque in the brain, exacerbating microglial activation, neuroinflammation, tau phosphorylation, and oxidative stress. These mechanisms work in concert and reinforce each other, contributing to the typical pathological changes in AD in the brain. Therefore, the identification of blood-borne proteins and the mechanisms involved in microglial activation and neuroinflammatory damage can be a promising therapeutic strategy for AD prevention. In this article, we review the current knowledge regarding the mechanisms of microglial activation-mediated neuroinflammation caused by the influx of blood-borne proteins into the brain via BBB disruption. Subsequently, the mechanisms of drugs that inhibit blood-borne proteins, as a potential therapeutic approach for AD, along with the limitations and potential challenges of these approaches, are also summarized.
血脑屏障（BBB）限制神经毒性血浆成分、血细胞和病原体进入大脑，从而保证神经元正常运作。血脑屏障受损会导致血源性蛋白质渗入，如凝血酶原、凝血酶、凝血酶原kringle-2、纤维蛋白原、纤维蛋白及其他有害物质。于是，小胶质细胞激活并释放促炎介质，导致神经元损伤，并通过神经炎症反应致使认知功能受损，这是阿尔茨海默病（AD）患者大脑中观察到的重要特征。此外，这些血源性蛋白质在大脑中与β淀粉样蛋白斑块聚集，加剧小胶质细胞激活、神经炎症、tau蛋白磷酸化和氧化应激。这些机制协同作用、相互强化，导致大脑中AD典型的病理变化。因此，识别血源性蛋白质以及小胶质细胞激活和神经炎症损伤所涉及的机制，可能是预防AD的一种有前景的治疗策略。在本文中，我们综述了目前关于血源性蛋白质通过血脑屏障破坏流入大脑所介导的小胶质细胞激活导致神经炎症机制的相关知识。随后，还总结了抑制血源性蛋白质的药物机制，作为AD的一种潜在治疗方法，以及这些方法的局限性和潜在挑战。
