Nature—Medin淀粉样蛋白是对抗Aβ沉积、血管损伤和认知缺陷的重要靶点

中文摘要

在50岁以上的几乎所有人的血管系统中都发现了medin淀粉样蛋白（MFG-E8蛋白的一个片段，也称为乳钙粘蛋白）的聚集体，这使其成为目前已知最常见的淀粉样蛋白。研究人员最近报道，medin也聚集在衰老的野生型小鼠的血管中，导致脑血管功能失调。在这里，他们在淀粉样β前体蛋白（APP）转基因小鼠和阿尔茨海默病患者中证明，medin与血管淀粉样β沉积共定位，并且在小鼠中，medin缺乏可以将血管淀粉样蛋白β沉积减少一半。此外，在小鼠和人脑中，MFG-E8在血管系统中高度富集，MFG-C8和medin水平都随着血管淀粉样蛋白-β负荷的严重程度而增加。此外，通过分析ROSMAP队列中566名患者的数据，他们发现阿尔茨海默病患者具有较高的MFGE8表达水平，这归因于血管细胞，并与认知能力下降的增加相关，与斑块和tau病理无关。在机制上，他们证明了medin与淀粉样蛋白-β直接相互作用，以促进其聚集，因为medin与β淀粉样蛋白形成异聚体纤维，影响β淀粉样纤维结构，并在体外和体内交叉播散β淀粉样蛋白的聚集。因此，medin可能是预防脑血管中淀粉样β沉积导致的血管损伤和认知功能下降的治疗靶点。

英文摘要

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer's disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 inpiduals in the ROSMAP cohort, we find that patients with Alzheimer's disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.