Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.

中文翻译：

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MFG-E8（LACTADHERIN）：一种与脑淀粉样血管病相关的新型标志物

β 淀粉样蛋白 (Aβ) 的大脑积聚是阿尔茨海默病 (AD) 和脑淀粉样血管病 (CAA) 的一个重要特征，尽管这些疾病之间的病理生理关系仍不清楚。许多蛋白质与沉积在实质斑块和/或脑血管中的 Aβ 相关。我们假设对这些蛋白质的研究将增加我们对这两种病理学之间的重叠和生物学差异的理解，并可能产生新的诊断工具和特定的治疗靶点。我们在脑 β 淀粉样变性 APP23 转基因小鼠模型中使用激光捕获显微切割方法结合质谱分析来特异性鉴定血管 Aβ 相关蛋白。我们重点关注在 Aβ 影响的脑血管系统中检测到的主要蛋白质之一：MFG-E8（乳脂肪球 - EGF 因子 8），也称为乳粘素。我们首先验证了 MFG-E8 在小鼠和人类大脑中的存在。免疫荧光和免疫印迹研究表明，APP23 小鼠脑中的 MFG-E8 水平高于 WT 小鼠。此外，在人死后 CAA 大脑的 Aβ 阳性血管中强烈检测到 MFG-E8，而实质 Aβ 沉积物中不存在 MFG-E8。另外还分析了诊断为 CAA 的患者、AD 患者和对照受试者的血清和脑脊液 (CSF) 中的 MFG-E8 水平。虽然各组之间的 MFG-E8 血清水平没有发现差异，但与对照组和 AD 患者相比，CAA 患者 CSF 中的 MFG-E8 浓度显着较低。最后，在人血管平滑肌细胞中，MFG-E8 可以抵抗含有 Dutch 突变的 Aβ40 肽治疗的毒性作用。总之，我们的研究表明 MFG-E8 与 CAA 病理学高度相关，并强调 MFG-E8 作为一种新的 CSF 生物标志物，可用于区分脑血管 Aβ 病理学和实质 Aβ 沉积。