Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Stroke. 2012 Feb;43(2):514-23. doi: 10.1161/STROKEAHA.111.627562. Epub 2011 Nov 23.
Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB.
We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels.
Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls.
Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.
脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）是一种退行性疾病，其特征是血脑屏障（Blood-brain barrier，BBB）中淀粉样β（Amyloid-β，Aβ）沉积。CAA 可导致神经血管损伤，包括脑叶出血、皮质微出血、缺血和脑表铁沉积症。我们假设 CAA 病理学部分是由于 Aβ损害 BBB。
我们根据 MRI 和临床发现，对 19 例急性卒中伴“可能的 CAA”患者进行了神经血管病理学特征分析。此外，我们还研究了 Aβ对分离大鼠脑微血管中紧密连接蛋白和基质金属蛋白酶（Matrix metalloproteases，MMPs）表达的影响。
19 例 CAA 患者中有 2 例存在无症状的 BBB 渗漏和后部可逆性脑病综合征，表明 BBB 通透性增加。除了白质变化，在 19 例 CAA 患者中有 4 例发现弥散异常提示腔隙性缺血；9 例中有 7 例观察到脑表铁沉积症。Aβ（40）降低了紧密连接蛋白 claudin-1 和 claudin-5 的表达，增加了 MMP-2 和 MMP-9 的表达。分析过表达人淀粉样前体蛋白的转基因小鼠的脑微血管发现，紧密连接和 MMP 蛋白的表达模式相同。与紧密连接和 MMP 表达和活性增加一致，与野生型对照的微血管相比，人淀粉样前体蛋白小鼠的脑微血管通透性增加。
我们的研究结果表明，Aβ 导致脑微血管紧密连接和 MMP 表达改变，损害 BBB 完整性。我们得出结论，Aβ 引起 BBB 渗漏，评估 BBB 通透性可能有助于 CAA 进展的特征描述，并作为治疗反应的替代标志物。
