Triposkiadis Filippos, Xanthopoulos Andrew, Boudoulas Harisios, Brutsaert Dirk L
European University Cyprus, 1516 Nicosia, Cyprus.
Department of Cardiology, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500 Larissa, Greece.
Biomolecules. 2025 Aug 8;15(8):1148. doi: 10.3390/biom15081148.
Aging is associated with aortic stiffening (AoSt), a condition characterized by diminished aortic elasticity that predisposes individuals to cognitive decline, including Alzheimer's disease (AD). Emerging evidence implicates medin, which is derived from milk fat globule-EGF factor 8 protein (MFG-E8), as a key link between AoSt and AD. Medin aggregates into aortic medial amyloid (AMA), which is found in approximately 97% of Caucasian individuals aged 50 and above, contributing to vascular inflammation, calcification, and loss of arterial elasticity. These changes may promote hyperpulsatile cerebral blood flow and impair glymphatic clearance, resulting in increased deposition of neurotoxic proteins, such as amyloid-β (Aβ) and possibly medin, which colocalizes with vascular Aβ in the brain. Medin enhances Aβ aggregation, generating heterologous fibrils, and thereby contributes to cerebrovascular dysfunction and neuroinflammation. This interaction (cross-seeding) may deteriorate amyloid pathology in both the vasculature and the parenchyma in AD. Furthermore, medin per se causes endothelial dysfunction, increases oxidative stress, and activates glial cells, promoting the development of a pro-inflammatory environment that enhances cognitive decline. In this manuscript, we contend that medin might act as a bridge connecting the age-related increase in aortic stiffness to AD, and therefore, medin might present a novel therapeutic target within this context. This hypothesis deserves experimental and clinical validation.
衰老与主动脉硬化（AoSt）相关，主动脉硬化的特征是主动脉弹性降低，使个体易患认知衰退，包括阿尔茨海默病（AD）。新出现的证据表明，源自乳脂肪球表皮生长因子8蛋白（MFG-E8）的medin是AoSt与AD之间的关键联系。Medin聚集成主动脉中层淀粉样蛋白（AMA），在约97%的50岁及以上白种人中可发现，它会导致血管炎症、钙化和动脉弹性丧失。这些变化可能会促进脑血流搏动增强并损害类淋巴系统清除功能，导致神经毒性蛋白，如淀粉样β蛋白（Aβ）以及可能与脑内血管Aβ共定位的medin沉积增加。Medin会增强Aβ聚集，生成异源纤维，从而导致脑血管功能障碍和神经炎症。这种相互作用（交叉播种）可能会使AD中血管和实质内的淀粉样病理状况恶化。此外，medin本身会导致内皮功能障碍，增加氧化应激，并激活神经胶质细胞，促进促炎环境的形成，进而加剧认知衰退。在本手稿中我们认为，medin可能是连接与年龄相关的主动脉僵硬增加和AD之间的桥梁，因此，在此背景下medin可能是一个新的治疗靶点。这一假设值得进行实验和临床验证。
