Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity
Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity
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DOI：
10.1093/brain/awv313
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发表时间：
2016-02-01
期刊：
影响因子：
14.5
通讯作者：
Samad, Tarek A.
中科院分区：
文献类型：
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作者：
Bales, Kelly R.;O'Neill, Sharon M.;Samad, Tarek A.
突出的脑淀粉样血管病经常在老年人的大脑中观察到，几乎普遍存在于阿尔茨海默病患者中。脑淀粉样蛋白血管病的特征是在小脑膜和皮质小动脉壁上积累较短的淀粉样- β亚型（主要是淀粉样- β(40)），这可能是导致老年人中风和痴呆的血管功能障碍的一个因素。我们使用具有明显脑淀粉样血管病的转基因小鼠来研究抗β淀粉样蛋白（40）选择性抗体ponezumab减轻脑血管中β淀粉样蛋白积累和急性恢复血管反应性的能力。通过活体多光子成像和免疫组织化学测量，对转基因小鼠长期给予ponezumab可显著减少脑轻脑膜和脑血管中的淀粉样蛋白和β淀粉样蛋白积累。通过对脑血管元素的富集，我们还测量了可溶性淀粉样蛋白- β的生化水平显著降低。我们假设，给药后血管淀粉样蛋白- β(40)的减少可能反映了ponezumab调动脑内淀粉样蛋白- β(40)间质液池的能力。急性地，ponezumab在年老的携带斑块的转基因小鼠中触发了间质液淀粉样蛋白- β(40)水平的显著和短暂的增加，但在年轻的动物中没有。我们还测量了急性给药后对血管反应性的有益影响，即使在有严重脑淀粉样血管病负担的血管中也是如此。综上所述，ponezumab在降低脑淀粉样血管病沉积率和恢复脑血管健康方面的有益作用有利于快速去除和/或中和淀粉样物质，否则可能对正常血管功能有害。
Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-beta isoform(s) (predominantly amyloid-beta(40)) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-beta(40) selective antibody, to attenuate amyloid-beta accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-beta accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-beta biochemically. We hypothesized that the reduction in vascular amyloid-beta(40) after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-beta(40) in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-beta(40) levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-beta species that may otherwise be detrimental to normal vessel function.