Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy.
Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy.
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DOI：
10.1161/strokeaha.111.627562
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发表时间：
2012-02
期刊：
影响因子：
8.3
通讯作者：
Schlachetzki F
中科院分区：
文献类型：
--
作者：
Hartz AM;Bauer B;Soldner EL;Wolf A;Boy S;Backhaus R;Mihaljevic I;Bogdahn U;Klünemann HH;Schuierer G;Schlachetzki F
脑淀粉样血管病（CAA）是一种退行性疾病，其特征是淀粉样蛋白-β（Aβ）在血脑屏障（BBB）中沉积。 CAA 会导致神经血管损伤，包括脑叶出血、皮质微出血、缺血和浅表含铁血黄素沉着症。我们假设 CAA 病理部分是由于 Aβ 损害 BBB 造成的。我们根据 MRI 和临床发现，对 19 名患有“可能 CAA”的急性中风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 对离体大鼠脑微血管中紧密连接蛋白和基质金属蛋白酶 (MMP) 表达的影响。 19 名 CAA 患者中有 2 名患有无症状 BBB 渗漏和后可逆性脑病综合征，表明 BBB 通透性增加。除了白质变化外，19 名 CAA 患者中有 4 名发现弥散异常，提示腔隙缺血； 9 名患者中有 7 名观察到浅表含铁血黄素沉着症。 Aβ40 降低紧密连接蛋白claudin-1 和claudin-5 的表达，并增加MMP-2 和MMP-9 的表达。对过度表达人类淀粉样前体蛋白的转基因小鼠脑微血管的分析揭示了紧密连接和 MMP 蛋白的相同表达模式。与紧密连接减少和 MMP 表达和活性增加相一致，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的通透性增加。我们的研究结果表明，Aβ 会导致脑微血管紧密连接和 MMP 表达的变化，从而损害 BBB 完整性。我们得出的结论是，Aβ 会导致 BBB 渗漏，评估 BBB 通透性可能有助于表征 CAA 进展并成为治疗反应的替代标志物。
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. Aβ40 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.