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 age^1,2, 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 individuals 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.

几乎所有 50 岁以上人类的脉管系统中都发现了 Medin 淀粉样蛋白（MFG-E8 蛋白的片段，也称为乳粘素）的聚集体 1,2 ，使其成为目前已知的最常见的淀粉样^蛋白。我们最近报道，medin 也会在衰老野生型小鼠的血管中聚集，导致脑血管功能障碍³。在这里，我们在淀粉样蛋白-β前体蛋白（APP）转基因小鼠和阿尔茨海默氏病患者中证明，medin与血管淀粉样蛋白-β沉积物共定位，并且在小鼠中，medin缺乏使血管淀粉样蛋白-β沉积物减少一半。此外，在小鼠和人脑中，MFG-E8 在血管系统中高度富集，并且 MFG-E8 和 Medin 水平随着血管淀粉样蛋白-β 负担的严重程度而增加。此外，通过分析 ROSMAP 队列中 566 名个体的数据，我们发现阿尔茨海默病患者的MFGE8较高表达水平，可归因于血管细胞，并与认知能力下降的增加相关，与斑块和 tau 病理无关。从机制上讲，我们证明medin直接与β淀粉样蛋白相互作用以促进其聚集，因为medin与β淀粉样蛋白形成异源原纤维，影响β淀粉样蛋白原纤维结构，并在体外和体内交叉产生β淀粉样蛋白聚集。因此，medin 可能成为预防因大脑血管中β-淀粉样蛋白沉积引起的血管损伤和认知能力下降的治疗靶点。