小柯机器人

德国神经退行性疾病中心Jonas J. Neher研究小组发现，medin在阿尔茨海默病中与血管β-淀粉样蛋白共同聚集。这一研究成果于2022年11月16日在线发表在国际学术期刊《自然》上。

据研究人员介绍，几乎所有50岁以上的人类血管中都发现了medin淀粉样蛋白（MFG-E8蛋白的一个片段，也被称为乳凝集素）的聚集物，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也在衰老的野生型小鼠血管中聚集，导致脑血管功能障碍。

研究人员在β-淀粉样前体蛋白（APP）转基因小鼠和阿尔茨海默病患者中证明了medin与血管β-淀粉样蛋白沉积物共同定位，并且在小鼠中，medin的缺乏会使血管β-淀粉样蛋白的沉积减少一半。此外，在小鼠和人脑中，MFG-E8在血管中高度富集，而且MFG-E8和medin的水平都随着血管β-淀粉样蛋白负担的严重程度而增加。此外，通过分析ROSMAP队列中566人的数据，研究人员发现阿尔茨海默病患者有较高的MFGE8表达水平，这归因于血管细胞，并与认知能力下降的增加措施有关，与斑块和tau病理无关。

在机制上，研究人员证明medin直接与β-淀粉样蛋白相互作用来促进其聚集，因为medin与β-淀粉样蛋白形成异源纤维，影响β-淀粉样蛋白的纤维结构，并在体外和体内交叉播撒β-淀粉样蛋白的聚集。因此，medin可能是一个治疗靶标，可用于预防β-淀粉样蛋白在大脑血管中沉积造成的血管损伤和认知能力下降。

附：英文原文

Title: Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Author: Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Hsler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, K. Peter R., Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, Neher, Jonas J.

Issue&Volume: 2022-11-16

Abstract: 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 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.

DOI: 10.1038/s41586-022-05440-3

Source: https://www.nature.com/articles/s41586-022-05440-3

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