Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy
Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy
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Aβ 免疫疗法治疗阿尔茨海默病：对 apoE 和脑血管病变的影响
DOI：
10.1007/s00401-014-1340-9
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发表时间：
2014
影响因子：
12.7
通讯作者：
James AR Nicoll
中科院分区：
文献类型：
--
作者：
Kenji Sakai;Delphine Boche;Roxana Carare;David Johnston;Clive Holmes;Seth Love;James AR Nicoll
Aβ免疫治疗阿尔茨海默病（AD）可清除Aβ斑块，增加脑淀粉样血管病（CAA）。在目前的临床试验中，淀粉样蛋白相关的影像学异常（阿里亚斯），由于CAA的恶化而引起的疼痛，是令人关注的副作用。我们的目的是评估Aβ转运蛋白载脂蛋白E（apoE）在Aβ免疫治疗后CAA恶化和CAA相关血管病变发展中的作用。将12例Aβ42免疫AD（iAD; AN 1792，Elan Pharmaceuticals）病例与28例未免疫AD（cAD）病例进行比较。对Aβ42、apoE、apoE E4和平滑肌肌动蛋白进行免疫组织化学定量，并分析CAA相关血管病变。Aβ免疫治疗与apoE从皮质斑块向脑血管壁的重新分布相关，反映了Aβ42分布的改变。免疫治疗后，柔脑膜血管的同心血管壁分裂增加了3倍（cAD 6.3 vs iAD 20.6%，P< 0.001），但平滑肌细胞异常没有差异。结果提示apoE参与了Aβ免疫治疗诱导的斑块清除和Aβ向脑血管的转运。免疫治疗与CAA相关的血管平滑肌损伤无关，但伴有血管壁分裂增加，可能反映了Aβ沉积增强和随后的清除。目前一些Aβ免疫治疗试验中发生的ARIA可能反映了这些血管变化的极端形式。
Aβ immunotherapy for Alzheimer’s disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %,P< 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.