Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy
Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy
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DOI：
10.1186/s40478-019-0662-1
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发表时间：
2019-01-28
影响因子：
7.1
通讯作者：
Naiki, Hironobu
中科院分区：
文献类型：
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作者：
Endo, Yoshinori;Hasegawa, Kazuhiro;Naiki, Hironobu
散发性脑淀粉样血管病（CAA）的特征是脑血管淀粉样β（A β）沉积，导致脑叶出血和痴呆。影响CAA发展的生物分子尚未完全表征。在这项研究中，我们对6例CAA患者和5例非CAA患者的软脑膜和皮质血管活检进行了蛋白质组分析，这些患者接受了大叶性脑血管病手术。结果发现CAA患者血管中A β、载脂蛋白E（apoE）、clusterin（CLU）、白蛋白、补体C4和玻连蛋白等6种蛋白表达均显著高于非CAA患者。所有CAA患者均检出ApoE和CLU。接下来，我们使用一种简单而强大的CAA体外模型，该模型概括了壁内动脉周围引流途径模型，研究了apoE和CLU对A β聚集早期的影响。我们发现，生理浓度的apoE和CLU延迟淀粉样蛋白的生长动力学的起始时间在浓度依赖性的方式。这些数据表明，载脂蛋白E和CLU可能作为细胞外伴侣，以抑制A β淀粉样蛋白沉积在CAA。
Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-beta (A beta) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including A beta, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of A beta aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit A beta amyloid deposition in CAA.