Schroeter Sally, Khan Karen, Barbour Robin, Doan Minhtam, Chen Ming, Guido Terry, Gill Davinder, Basi Guriqbal, Schenk Dale, Seubert Peter, Games Dora
Elan Pharmaceuticals, South San Francisco, California 94080, and Wyeth Pharmaceuticals, Cambridge, Massachusetts 02140, USA.
J Neurosci. 2008 Jul 2;28(27):6787-93. doi: 10.1523/JNEUROSCI.2377-07.2008.
In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta 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 VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta 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 Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.
除了实质淀粉样β蛋白（Aβ）斑块外，大多数阿尔茨海默病（AD）患者的脑脉管系统中也存在Aβ（脑淀粉样血管病，CAA）。最近对淀粉样前体蛋白转基因小鼠血管Aβ（V Aβ）的研究表明，用抗Aβ抗体进行被动免疫可能清除实质淀粉样蛋白，但会增加V Aβ和微出血的发生率。然而，抗体特异性和暴露水平对V Aβ和微出血率的影响尚未明确，也未确定任何明确的因果关系。本报告通过比较具有不同Aβ表位的抗体（3D6，Aβ（1 - 5）；266，Aβ（16 - 23））并进行3D6剂量反应研究，探讨了慢性被动免疫对PDAPP小鼠V Aβ和微出血的影响。使用同步的Aβ免疫组织化学和含铁血黄素检测来评估V Aβ和微出血。3D6以剂量依赖方式预防或清除V Aβ，但266无效。在最高3D6剂量下观察到V Aβ基本完全缺失，而在较低剂量下可见形态改变提示正在清除。高剂量3D6组微出血发生率增加，且局限于局灶性血管周围部位。这些部位与低剂量3D6组中形态改变且明显正在清除的Aβ沉积物共定位。我们的结果表明，被动免疫可降低V Aβ水平，调节抗体剂量可显著降低微出血发生率，同时仍可预防或降低V Aβ。这些观察结果提示，Aβ免疫疗法有可能减缓或阻止AD中与血管功能障碍相关的CAA发展进程。
