胰岛淀粉样多肽在神经血管单元中的作用机制研究进展

Advances in Research on the Mechanisms of Islet Amyloid Polypeptide in the Neurovascular Unit

摘要: 胰岛淀粉样多肽(Islet amyloid polypeptide, IAPP)是由胰岛β细胞产生，并与胰岛素协同分泌的一种激素。正常结构的单体IAPP对于神经血管单元(Neurovascular unit, NVU)产生正面影响。而胰岛素抵抗、肥胖和衰老等原因产生的错误折叠的IAPP，对NVU产生了各种不利的影响。在神经系统中错误折叠的IAPP聚集后通过激活多种信号通路、诱导氧化应激、激活炎症反应、影响细胞调控因子等多种机制，直接损害神经元和胶质细胞的形态和存活率使其结构塌陷功能丧失等。在脑血管系统中，错误折叠的IAPP沉积在血管壁和脑实质形成栓子，进而造成脑血管狭窄，灌注不足甚至出血；激活缺氧信号通路导致微血管功能障碍，病理性红细胞生成增多，血管平滑肌张力增加；损伤人脑血管周细胞正常功能等。错误折叠的IAPP通过以上病理过程加重脑栓塞、脑缺氧缺血发生并影响脑血管病后NVU的重建。综上所述，IAPP通过多种途径和分子机制影响了NVU中不同细胞类型，导致神经损伤，血管功能障碍，最终引发和加重脑血管疾病。深入研究IAPP在NVU中的作用机制对于理解脑血管病的发病机制、开发新的治疗策略及疾病预后的预测具有重要意义。

Abstract: Islet amyloid polypeptide (IAPP) is a hormone produced by pancreatic β-cells and co-secreted with insulin. Monomeric IAPP with a normal structure has a positive impact on the neurovascular unit (NVU). However, misfolded IAPP, resulting from factors such as insulin resistance, obesity, and aging, has various detrimental effects on the NVU. In the nervous system, misfolded IAPP aggregates and activates multiple signaling pathways, induces oxidative stress, triggers inflammatory responses, and affects cellular regulatory factors. These mechanisms directly damage the morphology and survival rates of neurons and glial cells, causing structural collapse and functional loss. In the cerebrovascular system, misfolded IAPP deposits in the vascular walls and brain parenchyma, forming emboli that lead to vascular narrowing, insufficient perfusion, and even hemorrhage. It also activates hypoxia signaling pathways, resulting in microvascular dysfunction, increased pathological erythropoiesis, and enhanced vascular smooth muscle tension. Additionally, it impairs the normal function of human brain pericytes. Through these pathological processes, misfolded IAPP exacerbates cerebral embolism and cerebral hypoxia-ischemia, affecting the reconstruction of the NVU after cerebrovascular disease. In summary, IAPP influences different cell types within the NVU through various pathways and molecular mechanisms, leading to neuronal damage and vascular dysfunction, ultimately triggering and worsening cerebrovascular diseases. In-depth research into the role of IAPP in the NVU is crucial for understanding the pathogenesis of cerebrovascular diseases, developing new therapeutic strategies, and predicting disease prognosis.