Zhang Yan-Li, Wang Juan, Zhang Zhi-Na, Su Qiang, Guo Jun-Hong
Department of Neurology, First Hospital of Shanxi Medical University; Department of Neurology, Sixth Hospital of Shanxi Medical University (General Hospital of Tisco), Taiyuan, Shanxi Province, China.
Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
Neural Regen Res. 2022 Nov;17(11):2355-2363. doi: 10.4103/1673-5374.335829.
Neurovascular dysfunction, as an integral part of Alzheimer's disease, may have an important influence on the onset and progression of chronic neurodegenerative processes. The blood-brain barrier (BBB) pathway is one of the main pathways that mediates the clearance of amyloid-beta (Aβ) in the brain parenchyma. A large number of studies have shown that receptors and ATP-binding cassette transporters expressed on endothelial cells play an important role in Aβ transport across the BBB, but the specific mechanism is not clear. In this review, we summarize the possible mechanisms of Aβ production and clearance, and in particular the relationship between Aβ and brain capillary endothelial cells. Aβ is produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions. Dysregulation of Aβ clearance is considered to be the main reason for the massive accumulation of Aβ in the brain parenchyma. Several pathways mediating Aβ clearance from the brain into the periphery have been identified, including the BBB pathway, the blood-cerebrospinal fluid barrier and arachnoid granule pathway, and the lymphoid-related pathway. Brain capillary endothelial cells are the key components of Aβ clearance mediated by BBB. Receptors (such as LRP1, RAGE, and FcRn) and ATP-binding cassette transporters (such as P-gp, ABCA1, and ABCC1) expressed on endothelial cells play a critical role in Aβ transcytosis across the BBB. The toxic effects of Aβ can induce dysregulation of receptor and transporter expression on endothelial cells. Excessive Aβ exerts potent detrimental cerebrovascular effects by promoting oxidative stress, inducing chronic inflammation, and impairing endothelial structure and functions. All of these are main causes for the reduction in Aβ clearance across the BBB and the accumulation of Aβ in the brain parenchyma. Therefore, studies on the interactions between Aβ and brain capillary endothelial cells, including their receptors and transporters, studies on inhibition of the toxic effects of Aβ on endothelial cells, and studies on promoting the ability of endothelial cells to mediate Aβ clearance may provide new therapeutic strategies for Aβ clearance in Alzheimer's disease.
神经血管功能障碍作为阿尔茨海默病的一个组成部分，可能对慢性神经退行性过程的发生和发展产生重要影响。血脑屏障（BBB）途径是介导脑实质中β淀粉样蛋白（Aβ）清除的主要途径之一。大量研究表明，内皮细胞上表达的受体和ATP结合盒转运蛋白在Aβ跨血脑屏障转运中起重要作用，但具体机制尚不清楚。在本综述中，我们总结了Aβ产生和清除的可能机制，特别是Aβ与脑毛细血管内皮细胞之间的关系。Aβ是在病理条件下通过淀粉样前体蛋白的淀粉样生成加工异常切割产生的。Aβ清除失调被认为是Aβ在脑实质中大量积累的主要原因。已经确定了几种介导Aβ从脑向周围清除的途径，包括血脑屏障途径、血脑脊液屏障和蛛网膜颗粒途径以及淋巴相关途径。脑毛细血管内皮细胞是血脑屏障介导的Aβ清除的关键组成部分。内皮细胞上表达的受体（如LRP1、RAGE和FcRn）和ATP结合盒转运蛋白（如P-gp、ABCA1和ABCC1）在Aβ跨内皮细胞转运中起关键作用。Aβ的毒性作用可诱导内皮细胞上受体和转运蛋白表达失调。过量的Aβ通过促进氧化应激、诱导慢性炎症以及损害内皮结构和功能，对脑血管产生强大的有害影响。所有这些都是血脑屏障Aβ清除减少和Aβ在脑实质中积累的主要原因。因此，研究Aβ与脑毛细血管内皮细胞之间的相互作用，包括它们的受体和转运蛋白，研究抑制Aβ对内皮细胞的毒性作用，以及研究促进内皮细胞介导Aβ清除的能力，可能为阿尔茨海默病中Aβ清除提供新的治疗策略。
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