Levites Yona, Smithson Lisa A, Price Robert W, Dakin Rachel S, Yuan Bin, Sierks Michael R, Kim Jungsu, McGowan Eileen, Reed Dana Kim, Rosenberry Terrone L, Das Pritam, Golde Todd E
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
FASEB J. 2006 Dec;20(14):2576-8. doi: 10.1096/fj.06-6463fje. Epub 2006 Oct 26.
A number of hypotheses regarding how anti-Abeta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Abeta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Abeta levels after a single peripheral dose of anti-Abeta antibodies to both wild-type (WT) and young non-Abeta depositing APP and BRI-Abeta42 mice. The rapid rise in plasma Abeta observed after antibody (Ab) administration is attributable to prolongation of the half-life of Abeta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Abeta, we find no evidence that total brain Abeta levels are significantly altered. Surprisingly, cerebral spinal fluid Abeta levels transiently rise, and when Ab:Abeta complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Abeta, these data provide a framework to evaluate proposed mechanisms of Abeta attenuation mediated by peripheral administration of an anti-Abeta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Abeta or targeting a low abundance aggregation intermediate.
关于抗β淀粉样蛋白（Aβ）抗体如何改变淀粉样蛋白沉积，已经提出了许多假说，但对于Aβ免疫疗法的作用机制尚无共识。我们研究了单次外周给予抗Aβ抗体后，野生型（WT）以及年轻的非Aβ沉积型APP和BRI-Aβ42小鼠体内的结合特性、药代动力学、脑通透性以及Aβ水平的变化。抗体（Ab）给药后血浆Aβ的快速升高归因于与抗体结合的Aβ半衰期的延长。只有极小部分的抗体进入大脑，并且尽管血浆Aβ显著增加，但我们没有发现总脑Aβ水平有明显改变的证据。令人惊讶的是，脑脊液Aβ水平短暂升高，并且当将Ab：Aβ复合物直接注射到小鼠侧脑室时，它会迅速从大脑清除到血浆中并保持稳定。从Aβ每日更新的角度来看，这些数据为评估在被动免疫模式下有效的抗Aβ单克隆抗体（mAb）外周给药介导的Aβ衰减机制提供了一个框架。这些定量数据表明，mAb要么间接增强Aβ的清除，要么靶向低丰度的聚集中间体。
