Aβ peptide immunization restores blood-brain barrier integrity in Alzheimer disease
Aβ peptide immunization restores blood-brain barrier integrity in Alzheimer disease
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DOI：
10.1096/fj.05-3956com
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发表时间：
2006-03-01
期刊：
影响因子：
4.8
通讯作者：
Jefferies, Wilfred A.
中科院分区：
文献类型：
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作者：
Dickstein, Dara L.;Biron, Kaan E.;Jefferies, Wilfred A.
据报道，β 淀粉样蛋白 (Aβ) 肽免疫或 Aβ 抗体被动免疫可减少斑块负担、神经炎性营养不良、早期 Tau 病理、小胶质细胞增生以及逆转学习和记忆缺陷。这就产生了一个中心悖论：外周组织中的疫苗接种如何减少大脑中的斑块负担？目前还没有对这些现象提出单一的解释。为了协调这些观察结果，我们证明在 Tg2576 阿尔茨海默病 (AD) 模型小鼠中，血脑屏障 (BBB)（大脑和血液之间的结构屏障）的完整性受到损害。我们在 AD 型神经病理学发作之前和之后用 Aβ 免疫 Tg2576 小鼠，观察到免疫小鼠的 BBB 通透性、淀粉样蛋白负荷和小神经胶质细胞增生有所减少。结论是，AD 小鼠中 BBB 的完整性被破坏，并且在 Aβ 免疫后，免疫系统会清除大脑中来源的 Aβ，就像在缺乏屏障的外周器官中一样。一旦 A beta 被移除，BBB 的完整性就会恢复。因此，这些数据为理解免疫系统如何清除 AD 大脑中的淀粉样蛋白沉积物提供了一个知识框架，并提出了限制淀粉样蛋白病疾病进展的新策略。
Immunization with amyloid beta (A beta) peptides or passive immunization with antibodies against A beta has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, microgliosis as well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood-brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with A beta before and after the onset of AD-type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after A beta immunization the immune system clears A beta from sources in the brain as it would in peripheral organs lacking barriers. Once A beta is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.