Medin co-aggregates with vascular amyloid-β in Alzheimer's disease.
Medin co-aggregates with vascular amyloid-β in Alzheimer's disease.
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DOI：
10.1038/s41586-022-05440-3
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发表时间：
2022-12
期刊：
影响因子：
64.8
通讯作者：
Neher, Jonas J.
中科院分区：
文献类型：
--
作者：
Wagner, Jessica;Degenhardt, Karoline;Veit, Marleen;Louros, Nikolaos;Konstantoulea, Katerina;Skodras, Angelos;Wild, Katleen;Liu, Ping;Obermueller, Ulrike;Bansal, Vikas;Dalmia, Anupriya;Haesler, 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.
在几乎所有50岁以上的人的血管中发现了medin淀粉样蛋白（蛋白MFG-E8的片段，也称为乳粘蛋白）的聚集体，使其成为目前已知的最常见的淀粉样蛋白。我们最近报道说，medin也聚集在老年野生型小鼠的血管中，导致脑血管功能障碍。在这里，我们证明了在淀粉样蛋白-β前体蛋白（APP）转基因小鼠和阿尔茨海默病患者中，medin与血管淀粉样蛋白-β沉积物共定位，并且在小鼠中，medin缺乏可使血管淀粉样蛋白-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，并且MFG-E8和medin水平均随着血管淀粉样蛋白-β负荷的严重程度而增加。此外，分析来自ROSMAP队列中566名个体的数据，我们发现阿尔茨海默病患者具有较高的MFGE 8表达水平，这可归因于血管细胞，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，我们证明了medin直接与淀粉样蛋白-β相互作用以促进其聚集，因为medin与淀粉样蛋白-β形成异源原纤维，影响淀粉样蛋白-β原纤维结构，并在体外和体内交叉种子淀粉样蛋白-β聚集。因此，medin可能是预防脑血管中淀粉样蛋白-β沉积导致的血管损伤和认知下降的治疗靶点。Medin在小鼠模型和阿尔茨海默病患者中促进β淀粉样蛋白血管聚集体的形成，并与血管缺陷和认知能力下降有关。
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, 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 dysfunction. 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. Medin promotes the formation of vascular aggregates with amyloid-β in mouse models and in human patients with Alzheimer’s disease, and is associated with vascular defects and cognitive decline.
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影响因子：
25
作者：
Habib, Naomi;McCabe, Cristin;Medina, Sedi;Varshavsky, Miriam;Kitsberg, Daniel;Dvir-Szternfeld, Raz;Green, Gilad;Dionne, Danielle;Nguyen, Lan;Marshall, Jamie L.;Chen, Fei;Zhang, Feng;Kaplan, Tommy;Regev, Aviv;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
16.6
作者：
Iturria-Medina Y;Sotero RC;Toussaint PJ;Mateos-Pérez JM;Evans AC;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
DOI：
10.1074/jbc.m114.602177
发表时间：
2015-03-20
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Davies HA;Madine J;Middleton DA
通讯作者：
Middleton DA
影响因子：
34.7
作者：
Brown, Guy C.;Neher, Jonas J.
通讯作者：
Neher, Jonas J.
影响因子：
9.8
作者：
De Jager, Philip L.;Ma, Yiyi;Bennett, David A.
通讯作者：
Bennett, David A.