Immunotherapy reduces vascular amyloid-β in PDAPP mice
Immunotherapy reduces vascular amyloid-β in PDAPP mice
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DOI：
10.1523/jneurosci.2377-07.2008
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发表时间：
2008-07-02
影响因子：
5.3
通讯作者：
Games, Dora
中科院分区：
文献类型：
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作者：
Schroeter, Sally;Khan, Karen;Games, Dora
除了实质淀粉样蛋白-β（A β）斑块外，阿尔茨海默病（AD）的特征在于大多数患者的脑血管系统中存在A β [脑淀粉样蛋白血管病（CAA）]。最近在淀粉样前体蛋白转基因小鼠中研究血管A β（VA β）的研究表明，抗A β抗体的被动免疫可能清除实质淀粉样蛋白，但增加VA β和微出血的发生率。然而，抗体特异性和暴露水平对VA β和微出血率的影响尚未得到很好的确定，也没有确定任何明确的因果关系。本报告通过比较具有不同A β表位（3D 6，A β（1-5）; 266，A β（16-23））的抗体并进行3D 6剂量反应研究，检查了慢性被动免疫对PDAPP小鼠中VA β和微出血的影响。同时使用A β免疫组织化学和含铁血黄素检测评估VA β和微出血。3D 6以剂量依赖性方式预防或清除VA β，而266则无作用。在最高3D 6剂量下观察到基本上完全不存在VA β，而在较低剂量下观察到提示持续清除的形态学改变。高剂量3D 6组的微出血发生率增加，仅限于局灶性血管周围部位。这些与A β沉积物共定位，在较低剂量3D 6组中具有改变的形态和表观清除率。我们的研究结果表明，被动免疫可以降低VA β水平，调节抗体剂量可以显着减轻微出血的发生率，同时仍然预防或降低VA β。这些观察结果提高了A β免疫疗法可能减缓或停止与血管功能障碍有关的AD中CAA发展的可能性。
In addition to parenchymal amyloid-beta (A beta) plaques, Alzheimer's disease (AD) is characterized by A beta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A beta(VA beta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A beta antibodies may clear parenchymal amyloid but increase VA beta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA beta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VA beta and microhemorrhage in PDAPP mice by comparing antibodies with different A beta epitopes (3D6, A beta(1-5); 266, A beta(16-23)) and performing a 3D6 dose-response study. VA beta and microhemorrhage were assessed using concomitant A beta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA beta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA beta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with A beta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA beta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA beta. These observations raise the possibility that A beta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.